Drugs in Clinical Pipeline: Neratinib | Dual Kinase Inhibitor | Breast Cancer Drug | EGFR Inhibitor | ERBB2 Inhibitor

Neratinib [(2E)-N-[4-[[3-Chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide] is an orally available small-molecule irreversible inhibitor of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2; also known as erbB2, CD340, ERBB2, HER2/neu) tyrosine kinases (TKs) [1, 2].

Neratinib : 2D and 3D Structure

It also blocks activity of HER4 (also known as erbB4). In vitro, it potently and selectively inhibits the erb-B receptor TKs at nanomolar concentrations (IC₅₀ ERBB2, EGFR = 59, 92 nM, respectively).

Osimertinib | Mutant Selective EGFR Inhibitor | Kinase Inhibitor | Orphan Drug | Treatment for NSCLC

Osimertinib [N-[2-[2-(dimethylamino)ethyl-methylamino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide] is an oral, small molecule, irreversible and mutant-selective inhibitor of epidermal growth factor receptor (EGFR) kinase activity. Chemically, Osimertinib is a mono-anilino-pyrimidine compound that is structurally and pharmacologically distinct from all other third-generation tyrosine kinase inhibitors (TKIs) including CO-1686 and WZ4002 [1, 2].

Osimertinib: 2D and 3D Structure

Osimertinib is designed in such a manner that it irreversibly and selectively targets both sensitizing and resistant-T790M mutant EGFR whilst harboring less activity towards wild-type EGFR. Osimertinib has been developed to target the EGFR T790M mutation that is often present in NSCLC patients with acquired EGFR TKI resistance, while sparing wild-type EGFR. 

Osimertinib was granted US FDA breakthrough therapy designation, orphan drug status and fast track status for non-small cell lung cancer (NSCLC) in 2014, and was granted US FDA priority review designation by early September 2015. In May 2015, Osimertinib was granted accelerated assessment status in the same indication in the EU, and received priority review status in Japan in the third quarter of 2015. 

Osimertinib has been designed to target the EGFR T790M mutation that is often present in NSCLC patients with acquired EGFR TKI resistance, while sparing wild-type EGFR. In November 2015, the tablet formulation of osimertinib was granted accelerated approval in the USA for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC who have progressed on or after EGFR TKI therapy [1].

Dosages and Approvals:

In Nov 2015, Osimertinib (Tradename: Tagrisso) a third-generation EGFR TKI that targets tumours with certain EGFR mutations, including T790M,got an  accelerated approval from the US FDA for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC (as detected by an FDA-approved test) who have progressed on or after EGFR TKI therapy.

The recommended dosage of Osimertinib is 80 mg once daily until unacceptable toxicity or disease progression (PD). Osimertinib tablets (available as 40 and 80 mg) can be taken with or without food, or in patients who have difficulty swallowing solids, dispersed in about 50 mL of noncarbonated water and immediately consumed or administered via nasogastric tube. 

A joint effort of AstraZeneca and University of Cambridge since 2014 is credited with discovery of Osimertinib, where the university’s researchers gain access to key compounds from AstraZeneca’s investigation pipeline, including Osimertinib. In October 2015, AstraZeneca entered into a collaborative agreement with Eli Lilly to investigate the use of Osimertinib as combination therapy (with Ramucirumab or Necitumumab) in patients with solid tumours.

Osimertinib Synthesis

J Med Chem 2014, 57(20), 8249-8267: It is one of the earliest reported synthetic route for Osimertinib. The article details the design, discovery and activity of Osimertinib and its various analogues.

Starting Material (Route 1):

Route 2: Shorter with better yields too !!!

 

Final Synthesis:

Identifications:

1H NMR (Estimated) for Osimertinib

Experimental: ¹H NMR (400 MHz, DMSO, 22 °C) δ 2.21 (6H, s), 2.29 (2H, t), 2.72 (3H, s), 2.89 (2H, t), 3.86 (3H, s), 3.92 (3H, s), 5.77 (1H, dd), 6.27 (1H, dd), 6.43 (1H, dd), 7.04 (1H, s), 7.15 (1H, t), 7.2-7.27 (2H, m), 7.53 (1H, d), 7.91 (1H, s), 8.24 (1H, d), 8.33 (1H, d), 8.68 (1H, s), 9.14 (1H, s), 10.22 (1H, s).

13C-NMR (Estimated) for Osimertinib

Experimental: ¹³C NMR (176 MHz, DMSO, 22 °C) δ 32.8, 42.6, 45.1, 55.7, 56.0, 56.8, 105.3, 107.1, 110.4, 112.4, 113.3, 120.8, 121.2, 121.9, 125.3, 125.5, 125.9, 127.7, 132.4, 133.8, 137.3, 137.7, 145.8, 157.6, 158.9, 159.8, 161.5, 162.3.

Sideeffects: The most common adverse events (AEs) of any grade with Osimertinib (occurring with greater than 20 % incidence) were diarrhea (47 %), rashes and acne (group term; 40 %), nausea (22 %), decreased appetite (21 %) and dry skin (20 %). The incidences of some adverse events, including diarrhoea and rash, increased in a dose-dependent fashion.

Based on clinical trial data, the US prescribing information for Osimertinib carries warnings and precautions regarding the increased risk of ILD/pneumonitis, QTc interval prolongation and cardiomyopathy during treatment.

Results from clinical trials reveal that pneumonitis-like events were reported in six patients (2.4 %), all of whom stopped treatment and had resolved or were resolving at the time of analysis. Eleven patients (4.3 %) experienced prolongation of QTc interval and six patients (2.4 %) reported hyperglycaemia during Osimertinib treatment; none of these patients required dosage reduction or drug discontinuation. Of the seven fatal adverse events with Osimertinib, one case of pneumonia was considered to be possibly treatment-related.

References:
1. Greig, S. L. Osimertinib: First Global Approval. Drugs 2016, 76(2), 263-73. (FMO only)
2. Finlay, M. R.; et. al. Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. J Med Chem 2014, 57(20), 8249-67. (FMO only)

Drugs in Clinical Pipeline: Canertinib

Canertinib [N-(4-((3-Chloro-4-fluorophenyl)amino)-7-(3-(morpholin-4-yl)propoxy) quinazolin-6-yl)prop-2-enamide] is an orally bio-available quinazoline compound with potential antineoplastic and radiosensitizing activities. Canertinib binds to the intracellular domains of epidermal growth factor receptor tyrosine kinases (ErbB family), irreversibly inhibiting their signal transduction functions and resulting in tumor cell apoptosis and suppression of tumor cell proliferation. This agent also acts as a radiosensitizing agent and displays synergistic activity with other chemotherapeutic agents.

Canertinib is a novel tyrosine kinase inhibitor developed for the treatment of certain solid cancers and has been designed to specifically inhibit all member of the ERBB-receptor family (ERBB1, ERBB2, ERBB3 and ERBB4) without blocking tyrosine kinase activity of many other receptors such as platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), and insulin receptor (INSR) [1].

It is an irreversible tyrosine-kinase inhibitor with activity against EGFR (IC₅₀ = 1.5 nM) and ErbB-2 (IC₅₀ = 9.0 nM) [2].

The activity of Canertinib is as follows: 

IC₅₀ (EGFR cell-free assay) = 1.5 nM

IC₅₀ (ErbB2 cell-free assay) = 9.0 nM

Common Name: Canertinib

Synonyms:  CI-1033; PD183805

IUPAC Name: N-(4-((3-Chloro-4-fluorophenyl)amino)-7-(3-(morpholin-4-yl)propoxy) quinazolin-6-yl)prop-2-enamide

CAS Number: 267243-28-7; 289499-45-2 (hydrochloride)

SMILES:C=CC(=O)NC1=C(C=C2C(=C1)C(=NC=N2)NC3=CC(=C(C=C3)F)Cl)OCCCN4CCOCC4.Cl.Cl 

Mechanism of Action: Kinase Inhibitor; EGFR Inhibitor; ErbB2 Inhibitor; pan-ERBB Inhibitor

Indication: Various Cancers; Anti-tumor Therapy

Development Stage: Phase III

Company: Pfizer, Inc.

Canertinib, was designed as a pan-ERBB tyrosine kinase inhibitor. It inhibits all four ERBB receptor family members. Canertinib is an irreversible inhibitor that binds covalently to specific cysteine residues in the ATP-binding pocket such as cysteine 773 of EGFR, cysteine 784 of ERBB2 and cysteine 778 of ERBB4 thereby blocking the ATP binding site in the kinase domain of ERBB proteins, preventing their kinase activity and downstream signaling, it also prevents transmodulation of ERBB3 [3]. The covalent binding of canertinib results in prolonged suppression of ERBB activity [4]. Since canertinib blocks signaling through all members of the ErbB receptor family it is more efficient and has a broader antitumor effect than inhibitors that only prevent signaling from one of the ErbB receptors. Studies of human cancer cell lines indicate that canertinib results in potent and sustained inhibition of ERBB tyrosine kinase activity, thereby inhibition of Akt and MAPK pathways [5, 6]. Canertinib has been shown to inhibit growth and induce apoptosis in several cancer cell lines and xenografts [7, 8, 9]. It increases the effectiveness of radiation therapy [8]. In clinical studies canertinib has been shown to have acceptable side-effects. However, in phase II studies canertinib was only able to show modest effects on breast cancer and NSCLC patients [10, 11].

Canertinib is evaluated in clinical trials in the treatment of different solid cancers. Canertinib seems to be a promiscuous drug, a multi-kinase inhibitor, which is able to bind not only to the ERBB receptor family, but also to intracellular proteins. For instance, the Src kinase family consists of eight members, five of which are mainly expressed in hematopoeitic cells, Blk, Hck, Lck, Fyn, and Lyn, where the Lck protein seems to have a stronger binding to canertinib as shown in a protein binding assay [12].

Canertinib not only inhibits tyrosine phosphorylation but also enhances ubiquitinylation and accelerates endocytosis and subsequent intracellular destruction of ErbB-2 molecules. It alkylates a cysteine residue specific to ErbB receptors. The degradative pathway of ErbB receptor tyrosine kinases stimulated by tyrosine kinase inhibitors appears to be chaperone mediated, and thus is similar to the pathways activated by the heat shock protein 90 (Hsp90) antagonist geldanamycin and by stress-induced mechanisms [13].

It prevents smallpox viral replication in vitro and inhibits smallpox viral infection in vivo. [14]

Canertinib inhibited erbB receptor phosphorylation and induced growth inhibition and apoptosis at concentrations of 1 uM or more [15]

Canertinib has been demonstrated to increase the anti-proliferative effects of vemurafenib in the BRAF mutant melanoma cell lines, but little or no enhanced effect was noted with the combination treatment in the wild type melanoma cell lines [16].

Canertinib decreased the phosphorylation of an ErbB kinase signaling target p70S6-kinase T389 in a dose-dependent manner as well as inactivation of downstream signaling molecules in ALL cell lines. Canertinib also increased the expression of the pro-apoptotic protein BIM, caspase-3 cleavage followed by apoptosis, abrogated proliferation and increased sensitivity to BCR/ABL-directed TKIs [17].

Several clinical trials are testing the anti-tumor activity of canertinib in metastatic breast cancer [10], NSCLC [11] and advanced ovarian cancer [18].

References:

1. Slichenmyer, W. J.; et. al. CI-1033, a pan-erbB tyrosine kinase inhibitor. Semin. Oncol. 2001, 28(5 Suppl 16), 80-85.

2. Smaill, J. B.; et. al. Tyrosine kinase inhibitors. 17. Irreversible inhibitors of the epidermal growth factor receptor: 4-(phenylamino)quinazoline- and 4-(phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides bearing additional solubilizing functions. J. Med. Chem. 2000, 43(7), 1380-1397.

3. Fry, D. W., et. al. Specific, irreversible inactivation of the epidermal growth factor receptor and erbB2, by a new class of tyrosine kinase inhibitor. Proc. Natl. Acad. Sci. U.S.A. 1998, 95(20), 12022-12027.

4. Smaill, J. B.; et. al. Tyrosine kinase inhibitors. 15. 4-(Phenylamino)quinazoline and 4-(phenylamino)pyrido[d]pyrimidine acrylamides as irreversible inhibitors of the ATP binding site of the epidermal growth factor receptor. J. Med. Chem. 1999, 42(10), 1803-1815.

5. Djerf, E. A.; et. al. ErbB receptor tyrosine kinases contribute to proliferation of malignant melanoma cells: inhibition by gefitinib (ZD1839). Melanoma Res, 2009, 19(3), 156-166.

6. Djerf Severinsson, E. A.; et. al. The pan-ErbB receptor tyrosine kinase inhibitor canertinib promotes apoptosis of malignant melanoma in vitro and displays anti-tumor activity in vivo. Biochem. Biophys. Res. Commun. 2011. 414(3), 563-568.

7. Ako, E.; et. al. The pan-erbB tyrosine kinase inhibitor CI-1033 inhibits human esophageal cancer cells in vitro and in vivo. Oncol. Rep. 2007, 17(4), 887-893.

8. Nyati, M. K.; et. al. Radiosensitization by pan ErbB inhibitor CI-1033 in vitro and in vivo. Clin. Cancer Res 2004. 10(2), 691-700.;

9. Slichenmyer, W. J.; et. al. CI-1033, a pan-erbB tyrosine kinase inhibitor. Semin Oncol, 2001, 28(5 Suppl 16), 80-85.

10. Rixe, O.; et al.et. al. A randomized, phase II, dose-finding study of the pan-ErbB receptor tyrosine-kinase inhibitor CI-1033 in patients with pretreated metastatic breast cancer. Cancer Chemother. Pharmacol. 2009, 64(6), 1139-1148.

11. Janne, P. A.; et. al. Multicenter, randomized, phase II trial of CI-1033, an irreversible pan-ERBB inhibitor, for previously treated advanced non smallcell lung cancer. J. Clin. Oncol. 2007, 25(25), 3936-3944.

12. Fabian, M. A.; et. al. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat. Biotechnol. 2005, 23(3), 329-336.

13. Citri, A.; et. al. Drug-induced ubiquitylation and degradation of ErbB receptor tyrosine kinases: implications for cancer therapy. EMBO J. 2002, 21(10), 2407-2417.

14. Fauci, A. S.; et. al. Host-based antipoxvirus therapeutic strategies: turning the tables. J. Clin. Invest. 2005, 115(2), 231-233.

15. Hughes, D. P.; et. al. Essential erbB family phosphorylation in osteosarcoma as a target for CI-1033 inhibition. Pediatr. Blood Cancer. 2006, 46(5), 614-623.

16. Ng, Y. K.; et. al. Pan-erbB inhibition potentiates BRAF inhibitors for melanoma treatment. Melanoma Res. 2014, 24(3), 207-218.

17. Irwin, M. E.; et. al. Small molecule ErbB inhibitors decrease proliferative signaling and promote apoptosis in philadelphia chromosome-positive acute lymphoblastic leukemia. PLoS One 2013, 8(8), e70608.

18. Campos, S.; et. al. Multicenter, randomized phase II trial of oral CI-1033 for previously treated advanced ovarian cancer. J. Clin. Oncol. 2005, 23(24), 5597-5604.

19. Ciardiello, F.; et. al. novel approach in the treatment of cancer: Targeting the epidermal growth factor receptor. Clin. Cancer Res. 2001, 7(10), 2958-2970.

Drugs in Clinical Pipeline: Pelitinib

Pelitinib [(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide] is a 3-cyanoquinoline bearing  irreversible inhibitor of pan-ErbB tyrosine kinases. It is an orally active, potent and belongs to second generation of inhibitors. Pelitinib forms irreversible covalent bonds with epidermal growth factor receptors (EGFR) ErbB-1, -2 and -4, thereby inhibiting receptor phosphorylation and signal transduction and resulting in apoptosis and suppression of proliferation in EGFR-overexpressing tumor cell lines.

Pelitinib inhibits EGFR activity with the half maximal inhibition concentration IC₅₀ value of 38.5 nM in vitro [1]. It has been found to exert a potent anti-proliferative activity against tumor cells overexpressing EGFR, including NHEK, A431 and MDA-468 cells, with IC₅₀ values of 61 nM, 125 nM and 260 nM respectively; while it has also been found to potently inhibit EGF-induced phosphorylated EGFR (pEGFR) in A431 and NHEK cells with IC₅₀ values ranging from 20 nM to 80 nM [2].

The activity of Pelitinib is as follows:

IC₅₀ (EGFR enzyme assay) = 38.5 nM

IC₅₀ (SRC enzyme assay) = 282 nM

IC₅₀ (MEK/ERK enzyme assay) = 800 nM

IC₅₀ (ErbB2 enzyme assay) = 1.255 uM

IC₅₀ (Raf enzyme assay) = 3.353 uM

IC₅₀ (c-Met enzyme assay) = 4.1 uM

IC₅₀ (CDK4 enzyme assay) = greater than 20 uM

Common Name: Pelitinib

Synonyms:  EKB 569; EKB-569; WAY-EKB 569; WAY-EKB-569; WAY-172569

IUPAC Name: (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide

CAS Number: 257933-82-7

SMILES: CCOC1=C(C=C2C(=C1)N=CC(=C2NC3=CC(=C(C=C3)F)Cl)C#N) NC(=O)/C=C/CN(C)C

Mechanism of Action: Kinase Inhibitor; pan-ErbB Inhibitor; EGFR Inhibitor

Indication: Advanced Non-small Cell Lung Cancer; Colorectal Cancer

Development Stage: Phase II

Company: Wyeth / Pfizer

The epidermal growth factor receptor (EGFR) is a 170-kDa glycoprotein containing an extracellular ligand binding domain, a single transmembrane domain, and an intracellular tyrosine kinase domain. EGFR is a member of the ErbB family of receptors, a subfamily of four closely related receptor tyrosine kinases: EGFR (ErbB-1), HER2/c-neu (ErbB2), Her3 (ErbB-3) and Her4 (ErbB-4). On binding ligands, such as EGF or transforming growth factor-alpha (TGF-alpha), EGFR dimerizes with itself (homodimerization) or other members of the family such as c-erbB-2 (heterodimerization). Tyrosine kinase activity increases and the receptor phosphorylates tyrosine residues on itself (autophosphorylation). Phosphorylated EGF-R (pEGF-R), like other activated receptor tyrosine kinases, phosphorylates and activates several signal transduction pathways downstream of EGF-R, including phosphoinositide 3-kinase-AKT, extracellular signal-regulated kinase 1 and 2 (ERK1/2), and signal transducer and activator of transcription 3 (STAT3) pathways that ultimately control cell proliferation [3,4].

Mutations affecting EGFR expression or activity could result in cancer. Mutations that lead to EGFR overexpression (known as upregulation) or overactivity have been associated with a number of cancers, including lung cancer, anal cancers and glioblastoma multiforme. The somatic mutations involving EGFR leads to its constant activation, which produces uncontrolled cell division. Mutations, amplifications or misregulations of EGFR or family members are implicated in about 30% of all epithelial cancers.

Pelitinib or EGFR kinase inhibitor 86 irreversibly inhibits ErbB1 and ErbB2 by forming a covalent bond with Cys773 of the ATP-pocket. Since Pelitinib is very specific and water soluble, it has good bioavailability and specific reactivity towards its target, and therefore exerts potent anti-tumor effects and causes few side effects. Apart from inhibiting the EGFR kinase, it also displays activity towards HER2 in BT474 cell line. Reports of its use in solid tumors indicated that Pelitinib was well tolerated and had an acceptable pharmacokinetic safety profile. Toxicities associated with Pelitinib treatment were of gastrointestinal and sometimes of dermatological origin. A phase I-II dose-escalation study of Pelitinib in combination with chemotherapy FOLFOX4 and FOLFIRI pointed to some additional toxicities, including thrombocytopenia, and in cases of high doses haematological toxicities and neuropathy. But the overall responses were good as in the majority of the cases either complete or partial responses or stable disease was noted, although a minority showed signs of progressive disease as well. Currently, phase II studies in advanced colorectal cancers and combination studies of CCI-779 and Celecoxib in combination with Pelitinib are being set up to evaluate the potency of Pelitinib at a larger scale [5-9].

References:

1. Torrance, C. J.; et. al. Combinatorial chemoprevention of intestinal neoplasia. Nat Med 2000, 6(9), 1024-1028.

2. Nunes, M.; et. al. Phosphorylation of extracellular signal-regulated kinase 1 and 2, protein kinase B, and signal transducer and activator of transcription 3 are differently inhibited by an epidermal growth factor receptor inhibitor, EKB-569, in tumor cells and normal human keratinocytes. Mol Cancer Ther 2004, 3(1), 21-27.

3. Arteaga, C. L. The epidermal growth factor receptor: from mutant oncogene in nonhuman cancers to therapeutic target in human neoplasia. J Clin Oncol 2001, 19(18), 32S-40S.

4. Schlessinger, J. Cell signalling by receptor tyrosine kinases. Cell 2000, 103(2), 211-225.

5. Fabian, M. A.; et. al. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol 2005, 23(3), 329-336.

6. Tsou, H. R.; et. al. Optimization of 6,7-disubstituted-4-(arylamino)quinoline-3-carbonitriles as orally active, irreversible inhibitors of human epidermal growth factor receptor-2 kinase activity. J Med Chem 2005, 48(4), 1107-1131.

7. Hidalgo, M.; et. al. Phase I trials of EKB-569, an irreversible inhibitor of the epidermal growth factor receptor, in patients with advanced solid tumors. J Clin Oncol 2006, 24(15), 2252-2260.

8. Bonomi, P. Clinical studies with non-iressa EGFR tyrosine kinase inhibitors. Lung Cancer 2003, 41, S43-S48.

9. Tejpar, S.; et. al. Toxicity profile of the epidermal growth factor receptor inhibitor EKB-569 combined with fluoroacil-based chemotherapy in patients with advanced colorectal cancer. Cancer Abstr Summaries 2004, 5.

10. Tyner, J. W.; et. al. Blocking airway mucous cell metaplasia by inhibiting EGFR antiapoptosis and IL-3 transdifferentiation signals. J Clin Invest 2006, 116(2), 309-321.

11. Tejpar, S.; et. al. Phase 1/2a study of EKB-569, an irreversible inhibitor of epidermal growth receptor, in combination with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX-4) in patients with advanced colorectal cancer (CRC). Proc Am Soc Clin Oncol 2004, 3579.

12. Casado, E.; et. al. A phase I/IIA pharmacokinetic (PK) and serial skin and tumor pharmacodynamic (PD) study of the EGFR irreversible tyrosine kinase inhibitor EKB-569 in combination with 5-fluorouracil (5FU), leucovorin (LV) and irinotecan (CPT-11) (FOLFIRI regimen) in patients with advanced colorectal cancer (ACC). Proc Am Soc Clin Oncol 2004, 3543.

Drugs in Clinical Pipeline: BMS-599626

BMS-599626 [(S)-morpholin-3-ylmethyl(4-((1-(3-fluorobenzyl)-1H-indazol-5-yl)amino)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl) carbamate], a orally bioavailable small-molecule inhibitor of the human epidermal growth factor receptor (HER) kinase family, is able to modulate signaling and growth of tumor cells that depend on HER1 and/or HER2. 

It is being developed by Ambit Biosciences/Bristol Myers Squibb Pharmaceuticals, and is presently in Phase I trials for patients with advanced solid tumors.

Common Name: BMS-599626

Synonyms:  AC480; BMS-599626; AC 480; AC-480; BMS 599626; BMS599626

IUPAC Name: (S)-morpholin-3-ylmethyl (4-((1-(3-fluorobenzyl)-1H-indazol-5-yl)amino)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)carbamate

CAS Number: 714971-09-2; 873837-23-1 (hydrochloride)

Mechanism of Action: Kinase Inhibitior; EGFR Inhibitor; ERBB2 Inhibitor; ERBB4 Inhibitor

Indication: Various Cancers

Development Stage: Phase I

Company: Ambit Biosciences/Bristol Myers Squibb Pharmaceuticals

BMS-599626 inhibited HER1 and HER2 with IC50 of 20 and 30 nmol/L, respectively, and was highly selective when tested against a broad panel of diverse protein kinases. Biochemical studies suggested that BMS-599626 inhibited HER1 and HER2 through distinct mechanisms. BMS-599626 abrogated HER1 and HER2 signaling and inhibited the proliferation of tumor cell lines that are dependent on these receptors, with IC50 in the range of 0.24 to 1 micromol/L. BMS-599626 was highly selective for tumor cells that depend on HER1/HER2 and had no effect on the proliferation of cell lines that do not express these receptors. In tumor cells that are capable of forming HER1/HER2 heterodimers, BMS-599626 inhibited heterodimerization and downstream signaling. BMS-599626 had antitumor activity in models that overexpress HER1 (GEO), as well as in models that have HER2 gene amplification (KPL4) or overexpression (Sal2), and there was good correlation between the inhibition of receptor signaling and antitumor activity [1].

Phase I Study 

Researchers studied the safety, tolerability, and recommended dose of BMS-599626, an orally bioavailable inhibitor of the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases [2].

Methodology

Patients with advanced solid tumors that expressed epidermal growth factor receptor (EGFR) and/or HER-2 were recruited and enrolled in a Phase I, open-label, dose escalation trial of oral BMS-599626 starting at 100 mg/day given once daily for at least 28 days.


Findings

Forty-five patients received BMS-599626 (100–660 mg/day). Dose-limiting toxic effects were reported at 660 mg/day (grade 3 elevation of hepatic transaminases [two patients] and QTc interval prolongation [one patient]), therefore the recommended maximum tolerated dose was 600 mg/day. The most frequent drug-related toxic effects were diarrhea (30% of patients), anorexia (13%), asthenia (30%), and cutaneous toxic effects, including skin rash (30%). Pharmacokinetic analysis demonstrated Cmax and exposure to BMS-599626 in patients increased with dose. Eleven patients had stable disease and received BMS-599626 for =4 months. Serial skin and tumor biopsies taken before and after treatment revealed expected changes in pharmacodynamic biomarkers, indicating that the EGFR and HER-2 pathways were affected. Positron emission tomography imaging showed a metabolic response in 2 of 10 patients evaluated.

References:

1. Wong, T. W.; et. al. Preclinical antitumor activity of BMS-599626, a pan-HER kinase inhibitor that inhibits HER1/HER2 homodimer and heterodimer signaling. Clin Cancer Res 2006, 12(20 Pt 1), 6186-6193.
2. Soria, J. C.; et. al. Phase I safety, pharmacokinetic and pharmacodynamic trial of BMS-599626 (AC480), an oral pan-HER receptor tyrosine kinase inhibitor, in patients with advanced solid tumors. Ann Oncol 2012, 23(2), 463-471.
3. Gavai, A. V.; et. al. Discovery and preclinical evaluation of [4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid, (3S)-3-morpholinylmethyl ester (BMS-599626), a selective and orally efficacious inhibitor of human epidermal growth factor receptor 1 and 2 kinases. J Med Chem 2009, 52(21), 6527-6530.

Drugs in Clinical Pipeline: Allitinib

Allitinib [N-[4-[[3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl]amino]quinazolin-6-yl]acrylamide] is an orally active, highly selective irreversible inhibitor of the erbB family receptor tyrosine kinases (HER1, HER2, and HER4) [1]. In preclinical trials, the IC₅₀ values of Allitinib inhibiting EGFR and HER2 were 0.5 and 3 nM, respectively, which were 5-15-fold more potent than Afatinib and Dacomitinib. Allitinib could potently inhibit the EGFR T790M mutant, exhibiting an IC₅₀ value of 12 ± 2 nM, which is similar to Afatinib (IC₅₀ = 10 nM) and approximately 500-fold more potent than Lapatinib [1]. In human tumor xenograft models that expressed or overexpressed HER family members, Allitinib showed antitumor activities, especially against those with HER2 overexpression or EGFR T790M mutant tumors [1].

Allitinib an analogue of Lapatinib, is currently in clinical trials in China for the treatment of solid tumors. Pilot studies in our laboratory demonstrated that Allitinib was absorbed quickly, reaching C_max in 1.8-3.0 h. The mean half-life of Allitinib was estimated to be approximately 4 h. The concentration of Allitinib in plasma was low because of the poor solubility and permeability and extensive first-pass metabolism. High inter-patient variability was observed after oral dosing Allitinib tosylate tablets. An α, β-unsaturated carbonyl group was introduced to the structure of Allitinib, which was proved to be the key chemical group for the irreversible inhibition of EGFR and ErbB2. In vitro studies have demonstrated that the efficacy of Allitinib is superior to that of Lapatinib [2].

Common Name: Allitinib
Synonyms: AST-1306; AST1306; AST 1306; ALS1306

IUPAC Name: N-[4-[[3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl]amino]quinazolin-6-yl] acrylamide

CAS Number: 897383-62-9
Mechanism of Action: Kinase Inhibitior; EGFR Inhibitor; ERBB2 Inhibitor; ERBB3 Inhibitor
Indication: Various Cancers
Development Stage: Phase I (China)
Company: Allist Pharmaceuticals

Eidogen Sertanty Inc Provides Kinase Knowledge Base (KKB): a Collection of nearly 1.6 M Kinase Inhibitors.

Importantly, Allitinib functions as an irreversible inhibitor, most likely through covalent interaction with Cys797 and Cys805 in the catalytic domains of EGFR and ErbB2, respectively. Further studies showed that Allitinib inactivated pathways downstream of these receptors and thereby inhibited the proliferation of a panel of cancer cell lines. Although the activities of EGFR and ErbB2 were similarly sensitive to Allitinib, ErbB2-overexpressing cell lines consistently exhibited more sensitivity to Allitinib antiproliferative effects. Consistent with this, knockdown of ErbB2, but not EGFR, decreased the sensitivity of SK-OV-3 cells to Allitinib. In vivo, Allitinib potently suppressed tumor growth in ErbB2-overexpressing adenocarcinoma xenograft and FVB-2/N(neu) transgenic breast cancer mouse models, but weakly inhibited the growth of EGFR-overexpressing tumor xenografts. Tumor growth inhibition induced by a single dose of Allitinib in the SK-OV-3 xenograft model was accompanied by a rapid (within 2 h) and sustained (=24 h) inhibition of both EGFR and ErbB2, consistent with an irreversible inhibition mechanism. Taken together, these results establish Allitinib as a selective, irreversible ErbB2 and EGFR inhibitor whose growth-inhibitory effects are more potent in ErbB2-overexpressing cells [1].

Phase I Study

A phase I, open-label, dose-escalation study to evaluate the safety and tolerability, pharmacokinetics (PK), and preliminary anti-tumor effects of oral AST1306 is reported [3]. In addition the effects of food on PK was tested.

Methods

A modified Fibonacci 3 plus 3 dose-escalation design was employed to determine the dose-limiting toxicity (DLT) and recommended phase II dose (RP2D) in patients with advanced solid tumors. The following dose levels were investigated: once daily (QD) at two dose levels (400-and 800 mg), twice daily (BID) in five dose levels (600-, 800-, 1000-, 1200- and 1500 mg), and three times daily (TID) in three dose levels (800-, 1000- and 1200 mg). In the PK and extension study, at least eight patients per dose cohort in three dose levels (maximum tolerated dose [MTD], one or two doses level lower than the MTD) were enrolled to evaluate the PK profiles.

Results


Seventy-one patients were enrolled, with breast (n = 22) and lung cancers (n = 14) being the most common primary cancers. The most frequent drug-related adverse events were grade 1 to 3 diarrhea and rash, grade 1 to 2 fatigue. During dose escalation, the key DLT was grade 3 diarrhea observed in 5 patients at 1000 mg BID (n = 1), 1500 mg BID (n = 1), 800 mg TID (n = 1) and 1200 mg TID (n = 2). AST1306 was rapidly absorbed and had moderate to high clearance. PK concentration parameters increased with dose over the range evaluated, with no evidence of accumulation over time. Under fed conditions, the mean Tmax was prolonged, Cmax was increased, and AUC0-8 was raised. Of the 55 evaluable patients, 7 patients experienced partial responses, including 5 with breast cancer, 1 with lung cancer, and 1 with gastric cancer. The best response with stable disease for = 6 months was achieved in 7 patients.

Conclusions

Based on the DLT and PK profile, the RP2D was defined as 1000 mg TID with evidence of preliminary anti-tumor activity. Further studies are recommended.

References:

1. Xie, H.; et. al. AST1306, a novel irreversible inhibitor of the epidermal growth factor receptor 1 and 2, exhibits antitumor activity both in vitro and in vivo. PLoS One 2011, 6(7), e21487.
2. Lin, L.; et. al. Development and validation of a sensitive LC-MS/MS assay for the simultaneous quantification of allitinib and its two metabolites in human plasma. J Pharm Biomed Anal 2013, 86, 49-55.
3. Cao, J.; et. al. A phase I study of AST1306, a novel irreversible EGFR and HER2 kinase inhibitor, in patients with advanced solid tumors. J Hematol Oncol 2014, 7, 22.

Drugs in Clinical Pipeline: CUDC-101

CUDC-101 [7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide] is a novel molecule which simultaneously inhibits histone deacetylase (HDAC) and the receptor kinases epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) in cancer cells - all of which are overexpressed in many cancers. CUDC-101, currently being developed by Curis, Inc., and was in Phase I trail for the common type of especially aggressive head and neck cancer that is not caused by the human papilloma virus (HPV-) but rather by tobacco or alcohol.

Strengthened by its integrated histone deacetylase inhibition, CUDC-101 synergistically blocked key regulators of EGFR/HER2 signaling pathways, also attenuating multiple compensatory pathways, such as AKT, HER3, and MET, which enable cancer cells to escape the effects of conventional EGFR/HER2 inhibitors.  It potently blocks the receptor tyrosine kinases EGFR (aka HER1) and HER2 (IC50s = 2.4 and 16.4 nM, respectively). CUDC-101 also inhibits the activity of class I and class II HDACs at nanomolar concentrations (e.g., IC50s = 4.5, 12.6, 13.2, and 11.4 nM for HDAC1, 2, 4, and 5, respectively). It has only weak effects on over 60 other kinases when tested at 5 µM [1].

Cancer cells that have acquired resistance to single-target EGFR inhibitors through upregulation of AXL or loss of E-cadherin remain sensitive to CUDC-101, which inhibits MET- and AXL-mediated signaling, restores E-cadherin expression, and reduces cell migration. CUDC-101 also efficiently inhibited the proliferation of MET-overexpressing non-small cell lung cancer and gastric cancer cell lines and inhibited the migration and invasion of invasive tumor cells. Taken together, these results suggest that coupling HDAC and HER2 inhibitory activities to an EGFR inhibitor may potentially be effective in overcoming drug resistance and preventing cancer cell migration [2].

Phase I

In the phase 1 trial CUDC-101 was combined with the standard of care for treatment of head and neck cancer, which includes the chemotherapy drug cisplatin and radiation. Specifically, the study was performed in 12 medium- to high-risk head and neck cancer patients. At 18 months median follow up, one patient's cancer had worsened, two had died, and nine remained free of disease. Testing of blood and tumor samples showed that CUDC-101 had indeed inhibited the action of EGFR, HDAC and HER2. Although the MTD was identified, a high rate of dose-limiting toxicity (DLT)-independent discontinuation of CUDC-101 suggests a need for alternate schedules or routes of administration [4].

References:

1. Lai, C. J.; et. al. CUDC-101, a multitargeted inhibitor of histone deacetylase, epidermal growth factor receptor, and human epidermal growth factor receptor 2, exerts potent anticancer activity. Cancer Res 2010, 70(9), 3647-3656.
2. Wang, J.; et. al. Potential advantages of CUDC-101, a multitargeted HDAC, EGFR, and HER2 inhibitor, in treating drug resistance and preventing cancer cell migration and invasion. Mol Cancer Ther 2013, 12(6), 925-936.
3. Cai, X.; et. al. Discovery of 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide (CUDc-101) as a potent multi-acting HDAC, EGFR, and HER2 inhibitor for the treatment of cancer. J Med Chem 2010, 53(5), 2000-2009.
4. Galloway, T. J.; et. al. A Phase I Study of CUDC-101, a Multitarget Inhibitor of HDACs, EGFR, and HER2, in Combination with Chemoradiation in Patients with Head and Neck Squamous Cell Carcinoma. Clin Cancer Res 2015, 21(7), 1566-1573.

Drugs in Clinical Pipeline: AZD8931

AZD8931 [2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-N-methylacetamide] has a unique pharmacologic profile providing equipotent inhibition of EGFR, erbB2, and erbB3 signaling and showing greater antitumor activity than agents with a narrower spectrum of erbB receptor inhibition in specific preclinical models.  AZD8931 is currently being evaluated in Phase I human clinical trials for the treatment of cancer.

Common Name: AZD8931
Synonyms: AZD-8931; AZD8931; AZD 8931; Sapitinib
IUPAC Name: 2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-N-methylacetamide
CAS Number: 848942-61-0
Mechanism of Action: Kinase Inhibitior; EGFR Inhibitor; ERBB2 Inhibitor; ERBB3 Inhibitor
Indication: Various Cancers
Development Stage: Phase I
Company: AstraZeneca

Deregulation of HER family signaling promotes proliferation and tumor cell survival and has been described in many human cancers. Simultaneous, equipotent inhibition of EGFR-, HER2-, and HER3-mediated signaling may be of clinical utility in cancer settings where the selective EGFR or HER2 therapeutic agents are ineffective or only modestly active. Docking studies based on a model of the HER2 kinase domain helped rationalize the increased HER2 activity seen with the methyl acetamide side chain present in AZD8931. AZD8931 exhibited good pharmacokinetics in preclinical species and showed superior activity in the LoVo tumor growth efficacy model compared to close analogues [1].

In vitro, AZD8931 showed equipotent, reversible inhibition of EGFR (IC(50), 4 nmol/L), erbB2 (IC(50), 3 nmol/L), and erbB3 (IC(50), 4 nmol/L) phosphorylation in cells. In proliferation assays, AZD8931 was significantly more potent than gefitinib or lapatinib in specific squamous cell carcinoma of the head and neck and non-small cell lung carcinoma cell lines. In vivo, AZD8931 inhibited xenograft growth in a range of models while significantly affecting EGFR, erbB2, and erbB3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation [2].


References:
1. Barlaam, B.; et. al. Discovery of AZD8931, an Equipotent, Reversible Inhibitor of Signaling by EGFR, HER2, and HER3 Receptors. ACS Med Chem Lett 2013, 4(8), 742-746.
2. Hickinson, D. M.; et. al. AZD8931, an equipotent, reversible inhibitor of signaling by epidermal growth factor receptor, ERBB2 (HER2), and ERBB3: a unique agent for simultaneous ERBB receptor blockade in cancer. Clin Cancer Res 2010, 16(4), 1159-1169.