Apatinib | Kinase Inhibitor | VEGFR-2 Inhibitor | KDR Inhibitor | Angiogenesis Inhibitor | Anti-Tumor Drug

Apatinib [N-[4-(1-cyano-cyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridine carboxamide] is an orally available, selective small molecule inhibitor of vascular endothelial growth factor-2 (VEGFR-2 also known as KDR) tyrosine kinase. It is more potent than Sunitinib in inhibiting VEGFR2 (IC₅₀ Apatinib, Sunitinib = 0.001, 0.005 uM) [1, 2].

Apatinib is an analogue of Valatinib and shows similar anti-angiogenic/anti-tumour efficacy. It binds with VEGFR-2 tyrosine kinase targeting the intracellular ATP binding site of the receptor, preventing phosphorylation and subsequent downstream signalling. Apatinib has shown a superior in vivo efficacy compared to Valatinib in xenograft models.

Apatinib has been approved by the Chinese Food and Drug Administration (CFDA) in October 2014 for the treatment of metastatic gastric carcinoma. It is an investigational cancer drug in many other countries including USA, EU etc and currently undergoing clinical trials as a potential targeted treatment for metastatic gastric carcinoma, metastatic breast cancer and advanced hepatocellular carcinoma.

Apatinib: 2D and 3D Structure

Angiogenesis, Tumor Angiogenesis and VEGFRs

Angiogenesis, the formation of new blood vessels from pre-existing ones, plays a central role in the process of tumor growth and metastasis. The proliferation of endothelium and formation of new blood vessels further the size of solid tumors. It is expected that blocking angiogenesis will be an efficient therapeutic approach against many tumor types.

Tumor angiogenesis plays a critical role in the malignant tumor growth and metastasis. When tumors grow beyond 1 mm³, angiogenesis or generation of vascular arborizations by budding from existing vessels is necessary to provide enough blood for the survival of tumor cells. The growth speed and tendency of metastasis of tumors are associated with the level of neovascularization factors and the quantity of nascent microvessels. Since the hypothesis “anti-angiogenesis therapy” was put forward by Folkman in early 1970s, people have made considerable progress in this field, and inhibiting angiogenesis of tumors has been universally accepted as a new anticancer strategy. 

Tyrosine kinase vascular endothelial growth factor (VEGF) and its receptor (VEGFR) play significantly important roles in angiogenesis of tumors, and they are both important targets in blocking angiogenesis of tumors. Vascular endothelial growth factor (VEGF) is the foremost factor in vivo promoting the angiogenesis. The binding of VEGF with vascular endothelial growth factor receptor (VEGFR) in endothelial cells leads to various reactions of angiogenesis, such as cells proliferation, cells metastasis, the increase of vascular permeability, and the move of endothelial cells precursors out of marrow. VEGFR family comprises VEGFR1 (Flt-1), VEGFR2 (KDR/Flk-1) and VEGFR3 (Flt-4). Promotion of the angiogenesis is mainly mediated by the bonded VEGF and VEGFR2 (KDR/Flk-1).

Compared with traditional cytotoxic drugs which inhibit the growth of tumors, angiogenesis targeting drugs are more specific and less toxic as well as helpful to overcome the drug resistance of tumors and can be used for the treatment of various tumors [3, 4].

Apatinib as Kinase Inhibitor

In vitro enzyme experiments showed that Apatinib was an even more selective inhibitor of VEGFR-2 than Sunitinib, with an IC₅₀ of 0.001 uM and 0.005 uM, respectively. Apatinib could also potently suppress the activities of Ret, c-Kit and c-Src with an IC₅₀ of 0.013 uM, 0.429 uM and 0.53 uM, respectively. Apatinib had no significant effects on EGFR, Her-2 or FGFR1 in concentrations up to 10 uM [1].

Summary

Common name: YN968D1; YN 968D1; YN-968D1

Trademarks: -

Molecular Formula: C24H23N5O

CAS Registry Number: 811803-05-1; 1218779-75-9 (mesylate)

CAS Name: N-[4-(1-cyano-cyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridine carboxamide

Molecular Weight: 397.48

SMILES:O=C(NC1=CC=C(C2(C#N)CCCC2)C=C1)C3=CC=CN=C3NCC4=CC=NC=C4

InChI Key: WPEWQEMJFLWMLV-UHFFFAOYSA-N

InChI: InChI=1S/C24H23N5O/c25-17-24(11-1-2-12-24)19-5-7-20(8-6-19)29-23(30)21-4-3-13-27-22(21)28-16-18-9-14-26-15-10-18/h3-10,13-15H,1-2,11-12,16H2,(H,27,28)(H,29,30)

Mechanism of Action: Kinase Inhibitor; KDR Inhibitor; Multi-Kinase Inhibitor

Activity: Treatment of Metastatic Gastric Carcinoma; Anti-cancer Agents; Angiogenesis Inhibitors

Status: Launched 2014 (China)

Chemical Class: Small-molecules; Nitrile containing; Pyrimidine containing

Originator: Advenchen Laboratories (USA)/ Jiangsu Hengrui Medicine Co. Ltd (China)

Apatinib Synthesis

US20040259916A1: It appears to be the industrial process.

Identification:

1H NMR (Estimated) for Apatinib

References:
1. Tian, S.; et al. YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo. Cancer Sci 2011, 102(7), 1374-80. (FMO only)
2. Chen, G. Six membered amino-amide derivatives an angiogenisis inhibitors. US20040259916A1
3. Yuan, K.; et al. The salts of n-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridyl methyl)amino-3-pyridinecarboxamide. WO2010031266A1
4. Sharma, P. S.; et al. VEGF/VEGFR pathway inhibitors as anti-angiogenic agents: present and future. Curr Cancer Drug Targets 2011, 11(5), 624-53. (FMO only)

Momelotinib | JAK1, JAK2 Inhibitor | Janus Kinase Inhibitor | Therapy for Myelofibrosis

Momelotinib [N-(cyanomethyl)-4-[2-[[4-(4-morpholinyl)phenyl]amino]-4-pyrimidinyl]-benzamide] is a small-molecule, ATP-competitive and highly selective inhibitor for Janus Kinase 1 (JAK1, IC₅₀ = 11 nM) and Janus Kinase 2 (JAK2, IC₅₀ = 18 nM). Momelotinib inhibited JAK1 and JAK2 equipotently, but had an IC₅₀ that was approximately ninefold higher for the closely related JAK3 (IC₅₀ = 155 nM) kinase as compared with JAK2.

Momelotinib: 2D and 3D Structure

In a ‘single-point’ screening assay that assesses the degree of enzyme inhibition at a specified Momelotinib concentration (100 nM or 1 uM), only eight kinases (JAK1, JAK2, CDK2/A, ROCK2, MAPK8, TBK1, PRKD1 and PRKCN) showed less than 50% at 100 nM [1].

Summary

Common name: CYT387; CYT 387; CYT-387; CYT 11387; CYT-11387; CYT11387

Trademarks:

Molecular Formula: C23H22N6O2

CAS Registry Number: 1056634-68-4

CAS Name: N-(Cyanomethyl)-4-[2-(4-morpholinoanilino)pyrimidin-4-yl]benzamide

Molecular Weight: 414.47

SMILES:O=C(NCC#N)C1=CC=C(C2=NC(NC3=CC=C(N4CCOCC4)C=C3)=NC=C2)C=C1

InChI Key: ZVHNDZWQTBEVRY-UHFFFAOYSA-N

InChI: InChI=1S/C23H22N6O2/c24-10-12-25-22(30)18-3-1-17(2-4-18)21-9-11-26-23(28-21)27-19-5-7-20(8-6-19)29-13-15-31-16-14-29/h1-9,11H,12-16H2,(H,25,30)(H,26,27,28)

Activity: Treatment of myelofibrosis; Anti-neoplastics Drug; Anti-inflammatory Agents

Status: Phase I/II

Originator: Gilead Sciences

Momelotinib Synthesis

US8486941B2: This is first disclosed synthesis for Momelotinib. It doesn't appear to be industrially optimized.

WO2015191846: The scheme is derived from the patent.

Identifications:

1H NMR (Estimated) for Momelotinib

13C NMR (Estimated) for Momelotinib

Experimental: ¹³C NMR (75.5 MHz, d₆-DMSO) δ 166.04, 162.34, 160.26, 159.14, 146.14, 139.87, 134.44, 132.73, 127.80, 126.84, 120.29, 117.49, 115.50, 107.51, 66.06, 49.16, 27.68.

References:
1. Pardanani, A.; et. al. CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients. Leukemia 2009, 23(8), 1441-1445.
2. Brown, B. H.; et. al. N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide hydrochloride salts. WO2015191846A1

3. Burns, C. J.; et. al. Phenyl amino pyrimidine compounds and uses thereof. US8486941B2

Drugs in Clinical Pipeline: Apitolisib

Apitolisib [(S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one] is a selective, potent, orally bioavailable inhibitor of Class I PI3 kinase (PI3K) and mTOR kinase (TORC1/2) with excellent pharmacokinetic and pharmaceutical properties. Apitolisib displayed excellent potency against class I PI3K isoforms (IC₅₀ PI3K-α, β, δ and γ = 4.8, 27, 6.7 and 14 nM) and mTOR kinase (IC₅₀ = 17 nM) and selectivity against a large panel of other kinases, including closely related PIKK family members DNA-PK (K_i = 623 nM), VPS34 (IC₅₀ = 2000 nM), c2alpha (IC₅₀ = 1300 nM), and c2beta (IC₅₀ = 794 nM) [1, 2].

References:
1. Sutherlin, D. P.; et. al. Discovery of a potent, selective, and orally available class I phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) kinase inhibitor (GDC-0980) for the treatment of cancer. J Med Chem 2011, 54(21), 7579-7587.
2. Wallin, J. J.; et. al. GDC-0980 is a novel class I PI3K/mTOR kinase inhibitor with robust activity in cancer models driven by the PI3K pathway. Mol Cancer Ther 2011, 10(12), 2426-2436.

Drugs in Clinical Pipeline: GSK143

GSK143 [2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5-carboxamide] is a potent and highly selective spleen tyrosine kinase (SYK) inhibitor (pIC₅₀ = 7.5) showing good efficacy in the rat Arthus model. The selectivity profile of GSK143 was determined against a panel of 66 protein kinases and none were inhibited within 10-fold of SYK activity. GSK143 is greater than 600-fold selective for SYK over ZAP-70 (pIC₅₀ = 4.7), the other member of the SYK kinase family [1].

The activity of GSK143 is as follows:

pIC₅₀(SYK enzyme assay) = 7.5

pIC₅₀(ZAP-70 enzyme assay) = 4.7

pIC₅₀(LCK enzyme assay) = 5.3

pIC₅₀(LYN enzyme assay) = 5.4

pIC₅₀(JAK1 enzyme assay) = 5.8

pIC₅₀(JAK2 enzyme assay) = 5.8

pIC₅₀(JAK3 enzyme assay) = 5.7

pIC₅₀(AURKB enzyme assay) = 4.8

Common Name: GSK143

Synonyms: GSK143; GSK-143; GSK 143

IUPAC Name: 

CAS Number: 1240390-27-5

SMILES:

Mechanism of Action: Kinase Inhibitor; SYK Inhibitor; Spleen Kinase Inhibitor

Indication: Various Cancers; Anti-inflammatory Drugs

Development Stage: Investigational

Company: GlaxoSmithKline

The progression of GSK143 was terminated due to a mutagenicity risk highlighted in the Ames assay, it remains one of the most selective SYK inhibitors disclosed to date and hence an excellent tool molecule for further evaluation of the SYK mechanism.

References:
1. Liddle, J.; et. al. Discovery of GSK143, a highly potent, selective and orally efficacious spleen tyrosine kinase inhibitor. Bioorg Med Chem Lett 2011, 21(20), 6188-6194.

Drugs in Clinical Pipeline: Vistusertib | mTOR Inhibitors | Kinase Inhibitors

Vistusertib [3-[2,4-Bis((3S)-3-methylmorpholin-4-yl)pyrido[5,6-e]pyrimidin-7-yl]-N-methylbenzamide] is an oral, potent and selective dual mTORC1/mTORC2 inhibitor with clear activity in in vivo and in vitro experimental models. It is under clinical trials against various cancers as monotherapy as well in combination with other anti-cancer agents such as Estrogen Receptor Positive (ER+) Metastatic Breast Cancer, Metastatic Renal Cancer, Glioblastoma Multiforme, Ovarian Cancer etc [1, 2].

Vistusertib: 2D and 3D Structure

mTOR as Target for Cancer Treatment

Growth factor/mitogenic activation of the phosphatidylinositol 3-kinase (PI3K)/AKT signalling pathway ultimately leads to the key cell cycle and growth control regulator mTOR, the mammalian target of rapamycin (alternatively referred to as FRAP (FKBP 12 and rapamycin associated protein), RAFTl (rapamycin and FKBP12 target 1), RAPTl (rapamycin target 1) - all derived from the interaction with the FK-506-binding protein FKBP 12, and SEP (sirolimus effector protein)) [3]. 

mTOR is a mammalian serine/threonine kinase of approximately 289 kDa in size and a member of the evolutionary conserved eukaryotic TOR kinases. The mTOR protein is a member of the PB-kinase like kinase (PIKK) family of proteins due to its C-terminal homology (catalytic domain) with PI3-kinase and the other family members, e.g. DNA-PKcs (DNA dependent protein kinase), ATM (Ataxia- telangiectasia mutated).

PI3K-Akt-mTOR pathway is one of the most frequently dysregulated pathways in cancer. The mammalian target of rapamycin (mTOR) is a key target in the development of antitumor therapies. The finding that mTOR can exist in an alternative, rapamycin insensitive, complex that signals to Akt opened up a new line of thinking for the researchers. The existence of both a rapamycin sensitive complex (mTORC1) and a rapamycin insensitive complex (mTORC2) may provide an explanation for the differences observed in the earlier research works. Rapamycin and its analogues have been shown to activate AKT signaling as a consequence of inhibition of the negative feedback loop downstream of mTORC1. Moreover, this is associated with a shorter time to progression in glioblastoma patients treated with rapamycin suggesting that dual mTORC1 and 2 inhibitors that inhibit AKT signaling could offer greater clinical benefit compared with rapalogues. In addition, dual mTORC1 and mTORC2 inhibitors may exhibit a broader spectrum of clinical activity [2].

 Vistusertib as mTOR Inhibitor

Vistusertib is a potent inhibitor of mammalian target of rapamycin (mTOR) kinase (IC₅₀ = 0.0028 uM) and displays a high level of selectivity against other members of the PIKK family (IC₅₀ PI3Kα = 3.8 uM, PI3Kβ, γ, δ greater than 29 uM, respectively). It was inactive against a general panel of over 200 kinases when tested at 10 uM. In in vivo studies, Vistusertib has been shown to modulate downstream markers of mTORC1 (inhibition of pS6 at Ser235/236 IC₅₀ = 0.2 uM) and mTORC2 (inhibition of pAKT at Ser473 IC₅₀ = 0.08 uM). Moreover, it has shown dose-dependent tumor growth inhibition in a mouse MCF7 xenograft model alongside modulation of mTORC1 and mTORC2 biomarkers.

Vistusertib showed excellent aqueous solubility (more than 600 uM), margin to the hERG (IC₅₀ = 47.5 uM) and was shown to have good oral exposure in both rat (100%) and mouse (40%). Vistusertib shows consistent exposure in rodents and a low turnover in human hepatocyte incubations and was subsequently selected for clinical development. Vistusertib is currently in Phase I/II [1, 2].

Dosages and Approvals:

Vistusertib (Tradename: -) is discovered and developed by Kudos Pharmaceuticals, later aquired by AstraZeneca. It is still under clinical trials.

Reported Activities for Vistusertib

IC₅₀ (mTOR enzyme assay) = 2.8 nM

IC₅₀ (PI3Kα enzyme assay) = 3.8 uM

IC₅₀ (PI3Kβ enzyme assay) = greater than 30 uM

IC₅₀ (PI3Kγ enzyme assay) = greater than 30 uM 

IC₅₀ (PI3Kδ enzyme assay) = greater than 29 uM

Summary

Common name: AZD2014; AZD-2014; AZD 2014; Vistusertib

Trademarks: -

Molecular Formula: C25H30N6O3

CAS Registry Number: 1009298-59-2

CAS Name: 3-(2,4-bis((S)-3-methylmorpholino)pyrido[2,3-d]pyrimidin-7-yl)-N-methylbenzamide

Molecular Weight: 462.54

SMILES:C[C@@H](COCC1)N1C2=NC(N3[C@@H](C)COCC3)=NC4=NC(C5=CC(C(NC)=O)=CC=C5)=CC=C42

InChI Key: JUSFANSTBFGBAF-IRXDYDNUSA-N

InChI: InChI=1S/C25H30N6O3/c1-16-14-33-11-9-30(16)23-20-7-8-21(18-5-4-6-19(13-18)24(32)26-3)27-22(20)28-25(29-23)31-10-12-34-15-17(31)2/h4-8,13,16-17H,9-12,14-15H2,1-3H3,(H,26,32)/t16-,17-/m0/s1

Mechanism of Action: Kinase Inhibitors; Dual mTOR Inhibitor

Activity: Various Cancers; Treatment for Breast Cancer; Anti-Cancer Agents

Status: Phase Trials (US)

Chemical Class: Small-molecules; Benzamides; Morpholines; Pyridines; Pyrimidines

Originator: AstraZeneca

Vistusertib Synthesis

WO2008023161A1: It is the oldest reported synthetic procedure for preparing quantitative amounts of Vistusertib and derivatives. The process involves sequential addition of 3S-Methylmorpholine at C4 and C2 position of trichloro intermediate, followed by using suitable boronic acid (or esters) via palladium mediated cross couplings to generate compounds. See also Ref 2.

Identifications:

1H NMR (Estimated) for Vistusertib

Sideeffects: The adverse events (AEs) were gastrointestinal symptoms such as nausea, mucositis, diarrhea and vomiting in 21/41 (51%), 20/41 (49%) 17/41 (42%), and 12/41 (29%) as reported by participants. However, less than 5% of these adverse events were grade 3 or 4. Nausea and vomiting were well controlled by antiemetics, such as domperidone, if necessary, and the grade 1-2 diarrhea did not consistently require treatment. Mucositis was grade 1-2 in most instances and patients responded to mouth-washes and did not require dose interruptions due to it. A predominantly maculopapular rash was observed in 17/41 (42%) of patients and less than 5% of these were grade 3 or higher. Lower respiratory tract infections were seen in 7/41 (17%) and it was grade 3 in only 1/41 (2%). Interestingly, no patients were diagnosed with pneumonitis.

The most common laboratory abnormality was anemia, with 7/41 (17%) having recorded grade 1-2 anemia; given the advanced cancer and degrees of co-morbidities in these patients, it was difficult to attribute this specifically to AZD2014. Hyperglycemia was seen in 5/41 (12%), 0/5 (0%), and 2/4 (50%) of patients treated at 50 mg BD, 70 mg BD and 100 mg BD, respectively [4].

Others: Readers can suggest.

References:

1. Guichard, S. M.; et. al. AZD2014, an Inhibitor of mTORC1 and mTORC2, Is Highly Effective in ER+ Breast Cancer When Administered Using Intermittent or Continuous Schedules. Mol Cancer Ther 2015, 14(11), 2508-2518. (free article)

2. Pike, K. G.; et. al. Optimization of potent and selective dual mTORC1 and mTORC2 inhibitors: the discovery of AZD8055 and AZD2014. Bioorg Med Chem Lett 2013, 23(5), 1212-1216. (FMO only)

3. Duggan, H. M. E.; et. al. 2-methylmorpholine pyrido-, pyrazo- and pyrimido-pyrimidine derivatives as mtor inhibitors. WO2008023161A1

4. Basu, B.; et. al. First-in-Human Pharmacokinetic and Pharmacodynamic Study of the Dual m-TORC 1/2 Inhibitor AZD2014. Clin Cancer Res 2015, 21(15), 3412-3419. (free article)

1 2 3

Drugs in Clinical Pipeline: GSK2636771 | PI3K Inhibitor | PI3Kbeta Inhibitor | Cancer Drug

GSK2636771 [2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic acid] is a potent, orally bioavailable and selective nanomolar inhibitor of the beta isoform of the 110 kDa catalytic subunit of class IA phosphoinositide-3 kinases (PI3K). GSK2636771 was more selective for PI3Kβ relative to other PI3K class I enzymes (IC₅₀: PI3Kβ = 0.89 nM) with greater than 900-fold selectivity over PI3Kα/PI3Kγ and more than 10-fold over PI3Kδ. It inhibits AKT phosphorylation and downstream signalling measured as decrease of PRAS40-, GSK3β-, and RPS6-phosphorylation in PTEN mutant cell lines [1].

GSK2636771: 2D and 3D Structure

The activity of GSK2636771 is as follows:

IC₅₀ (PI3Kβ enzyme assay) = 0.89 nM

Common Name: GSK2636771

Synonyms: GSK2636771; GSK-2636771; GSK 2636771

IUPAC Name: 2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic acid

CAS Number: 1372540-25-4

Mechanism of Action: Kinase Inhibitor; PI3K Inhibitor; PI3Kbeta Inhibitor

Indication: Various Cancers; Anti-Tumor Agents

Development Stage: Phase I/II
Company: GlaxoSmithKline

1H NMR (Estimated) for GSK2626771

References:
1. Arkenau, H. -T.; et. al. Abstract 2514: A phase I/II, first-in-human dose-escalation study of GSK2636771 in patients (pts) with PTEN-deficient advanced tumors. J Clin Oncol  2014, 32, (suppl).
2. Qu, J.; et. al. Benzimidazole derivatives as pi3 kinase inhibitors. WO2012047538A1 (For synthesis and activity see Example 31)

Drugs in Clinical Pipeline: Acalisib

Acalisib [(S)-2-(1-((7H-purin-6-yl)amino)ethyl)-6-fluoro-3-phenylquinazolin-4(3H)-one] is a potent, selective nanomolar inhibitor of the delta isoform of the 110 kDa catalytic subunit of class IA phosphoinositide-3 kinases (PI3K). 

Acalisib was more selective for PI3Kδ relative to other PI3K class I enzymes (IC₅₀: PI3Kδ = 12.7 nM; PI3Kα = 5441 nM; PI3Kβ = 3377 nM and PI3Kγ = 1389 nM). Acalisib was also 1000-fold more selective against PI3Kδ than against related kinases, such as CIIβ, hVPS34, DNAPK, and mammalian target of rapamycin (mTOR) [1].

Acalisib was also assayed for its potential binding interaction with kinases by screening a comprehensive panel of 393 kinases, including mutants, in the Ambit KINOMEscan. No binding outside of PI3K was observed at 10 µM Acalisib, further demonstrating a high degree of selectivity. Acalisib was considered active if less than 35% of binding to immobilized probes remained compared to DMSO control. Various PI3K isoforms have %control binding values in the 0.25-14 range. The next kinase target was PIP5K2B with a value of 49% [1].

Acalisib is under investigation for the treatment of lymphoid malignancies including non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) [2].

The activity of Acalisib is as follows:

IC₅₀ (PI3Kδ enzyme assay) = 12.7 nM

IC₅₀ (PI3Kα enzyme assay) = 5441 nM

IC₅₀ (PI3Kβ enzyme assay) = 3377 nM

IC₅₀ (PI3Kγ enzyme assay) = 1389 nM

IC₅₀ (DNA-PK enzyme assay) = 18.7 uM

IC₅₀ (mTOR enzyme assay) = greater than 1 uM

IC₅₀ (CIIβ enzyme assay) = greater than 1 uM

IC₅₀ (hVPS34 enzyme assay) = 12.6 uM

Common Name: Acalisib

Synonyms: GS-9820; GS9820; GS 9820; CAL-120; CAL 120; CAL120

IUPAC Name: (S)-2-(1-((7H-purin-6-yl)amino)ethyl)-6-fluoro-3-phenylquinazolin-4(3H)-one

CAS Number: 870281-34-8

Mechanism of Action: Kinase Inhibitor; PI3K Inhibitor; PI3Kdelta Inhibitor

Indication: Various Cancers; Anti-Tumor Agents; Autoimmune Disease Treatment

Development Stage: Phase I

Company: Gilead Sciences

References:
1. Shugg, R. P.; et. al. Effects of isoform-selective phosphatidylinositol 3-kinase inhibitors on osteoclasts: actions on cytoskeletal organization, survival, and resorption. J Biol Chem 2013, 288(49), 35346-35357.
2. Jun, S.; et. al. Interim Analysis Of A Phase 1B Study Evaluating The Safety Of GS-9820, A Second-Generation PI3Kd-Inhibitor, In Relapsed/Refractory Lymphoid Malignancies. 13th International Conference on Malignant Lymphoma. 17-20 June 2015 Lugano, Switzerland.

Drugs in Clinical Pipeline: Brigatinib

Brigatinib [5-chloro-4-N-(2-dimethylphosphorylphenyl)-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]pyrimidine-2,4-diamine] is an oral, potent and selective inhibitor of anaplastic lymphoma kinase (ALK). Brigatinib is reported to show activity against the both wild type ALK (IC₅₀ = 0.62 nM; K_i = 0.09 nM) as well as L1196M mutant (K_i = 0.08 nM) with about five-fold greater potency compared with Crizotinib {IC₅₀ (ALK) = 3.6 nM; K_i (ALK) = 0.69 nM; K_i (L1196) = 8.2 nM} [1]. Brigatinib was profiled against greater than 250 kinases by Reaction Biology Corporation (Malvern, PA) using the Kinase Hotspot assay, which utilizes 10 µM [³³P]-ATP, recombinant kinase domain, peptide substrate, and a single inhibitor concentration of 1 µM. Brigatinib inhibited eight kinases (FER, ROS, FLT3, FES, FAK, BRK, STK22D and CHK2) with IC₅₀ between 1-10 nM; 22 kinases with IC₅₀ between 10-100 nM. It inhibited EGFR with IC₅₀ = 129 nM but ErbB4 with an IC₅₀ value of 27 nM.

Brigatinib showed excellent preclinical activity against ALK and all 9 clinically-identified Crizotinib-resistant mutants tested [2].

Brigatinib is also a potent, reversible inhibitor of activated and T790M-mutant EGFR, yet it does not inhibit the native enzyme [3].

In October 2014, ARIAD Pharmaceuticals, Inc. announced that its investigational cancer medicine, Brigatinib, has received Breakthrough Therapy designation by the U.S. Food and Drug Administration (FDA) for the treatment of patients with anaplastic lymphoma kinase positive (ALK+) metastatic non-small cell lung cancer (NSCLC) who are resistant to crizotinib. This designation is based on results from the ongoing Phase 1/2 trial that show sustained anti-tumor activity of Brigatinib in patients with ALK+ NSCLC, including patients with active brain metastases.

The activity of Brigatinib is as follows:

IC₅₀ (ALK enzyme assay) = 0.62 nM

IC₅₀ (FER enzyme assay) = 1.3 nM

IC₅₀ (ROS enzyme assay) = 1.9 nM

IC₅₀ (FLT3 enzyme assay) = 2.1 nM

IC₅₀ (FES enzyme assay) = 3.4 nM

IC₅₀ (FAK enzyme assay) = 3.8 nM

IC₅₀ (BRK enzyme assay) = 4.1 nM

IC₅₀ (STK22D enzyme assay) = 4.3 nM

IC₅₀ (CHK2 enzyme assay) = 6.5 nM

Common Name: Brigatinib

Synonyms: AP26113; AP-26113; AP 26113

IUPAC Name: 5-chloro-4-N-(2-dimethylphosphorylphenyl)-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]pyrimidine-2,4-diamine

CAS Number: 1197953-54-0

SMILES:CN1CCN(CC1)C2CCN(CC2)C3=CC(=C(C=C3)NC4=NC=C(C(=N4)NC5=CC=CC=C5P(=O)(C)C)Cl)OC

Mechanism of Action: Kinase Inhibitor; ALK Inhibitor; Anaplastic Lymphoma Kinase Inhibitor; T790M Inhibitor

Indication: Various Cancers; Treatment of Non-Small Cell Lung Cancer

Development Stage: Phase I/II

Company: ARIAD Pharmaceuticals

The oncogenic fusion kinase echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) is present in ~4% of patients with non-small cell lung cancer (NSCLC). Chromosomal translocations involving ALK also occur in other cancers, including anaplastic large cell lymphomas and inflammatory myofibroblastic tumors. In all cases, the fusion partner (e.g., EML4) is believed to mediate ligand-independent oligomerization of ALK, resulting in constitutive ALK kinase activation. In cell line and genetically engineered mouse models, EML4-ALK serves as a potent oncogenic “driver,” and cancers with this translocation are highly sensitive to ALK kinase inhibition. Crizotinib (PF-02341066), a tyrosine kinase inhibitor (TKI) targeting ALK, was examined in a phase 1 trial where among 105 patients with EML4-ALK–positive NSCLC, crizotinib showed remarkable activity, with an objective response rate of 56% and a median progression-free survival of 9.2 mo. These results support the notion that lung cancers harboring EML4-ALK are highly susceptible to ALK-targeted therapies and demonstrate the properties of “oncogene addiction” to ALK [1].

Phase II Study {Anti-tumour Activity in ALK-positive NSCLC patients with Brain Metastasis} [5]

Concept: Central nervous system (CNS) progression has been observed in a significant proportion of patients treated with Crizotinib for ALK-positive Non-small cell lung cancer (NSCLC). More than 80% of patients with NSCLC and brain metastases achieved intracranial disease control after treatment with Brigatinib.

Methodology: Contrast-enhanced magnetic resonance imaging of the brain was done at baseline and at follow-up that was centrally reviewed by blinded independent neuroradiologists. Lesions having a longest diameter of 10 mm or greater were defined as measurable lesions. The post hoc analysis was done on data from 45 of the 49 patients identified with baseline brain metastases that had evaluable data at cut-off. The patients were among participants in a larger phase 1/2 single-arm, multicentre study of Brigatinib in patients with advanced malignancies. All patients received Brigatinib at total daily doses of 30 to 300 mg orally once daily.

The 49 patients identified with baseline brain metastasis and having evaluable data were on study a median of 56.1 weeks. Measurable brain metastases were reported for 16 patients and non-measurable brain metastases for 33 patients. Following treatment, 45 patients overall with brain involvement and a follow-up scan achieved median intracranial progression–free survival (PFS) of 22.3 months and the median duration of intracranial response in 16 patients with a response and a follow-up scan was 18.9 months.

Result: Intracranial response was reported for 8 (53%) patients with measurable brain metastases and for 9 (30%) patients identified with non-measurable lesions. Intracranial disease control was achieved by 13 (87%) patients with measurable and by 26 (87%) patients with non-measurable brain metastases.


Side-effects: Treatment-emergent adverse events were mild to moderate in severity and included nausea, diarrhoea, and fatigue that were reported by 29 (59%), 28 (57%) and 24 (49%) patients, respectively.

References:
1. Shaw, A. T.; et. al. Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK. Proc Natl Acad Sci U S A. 2011, 108(18), 7535-7540.
2. Gettinger, S.; et. al. 1292P Alk Inhibitor Ap26113 In Patients With Advanced Malignancies, Including Alk+ Non-Small Cell Lung Cancer (Nsclc): Updated Efficacy And Safety Data. Ann Oncol 2014, 25(suppl 4), iv455.
3.  Camidge, D. R.; et. al. First-in-human dose-finding study of the ALK/EGFR inhibitor AP26113 in patients with advanced malignancies: Updated results. J Clin Oncol 2013, 31(15), 8031.
4. Wang, Y.; et. al. Phosphorous derivatives as kinase inhibitors. US20150225436A1 (for structure and synthesis of AP26113, Example 122)
5. Kerstein, D. LBA4. Evaluation of anaplastic lymphoma kinase (ALK) inhibitor brigatinib [AP26113] in patients (pts) with ALK+ non-small cell lung cancer (NSCLC) and brain metastases. 2015 (article here)