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).

Drugs in Clinical Pipeline: Pacritinib | Dual Kinase Inhibitor | JAK2 Inhibitor | FLT3 Inhibitor

Pacritinib [11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene] is a novel low-molecular weight pyrimidine-based macrocycle with potent inhibitory activities against Janus Kinase 2 (JAK2) and Fms-Like Tyrosine Kinase-3 (FLT3). 

Pacritinib shows a unique kinase profile with selective inhibition of Janus Kinase-2 with IC₅₀ values of 23 and 19 nM against JAK2^WT and JAK2^V617F respectively and an IC₅₀ value of 22 nM gainst FLT3. Within the JAK family, Pacritinib has IC₅₀ values of 50, 520 and 1280 nM for TYK, JAK3 and JAK2, respectively, showing high preference for JAK2. The rest of the evaluated kinases showed less than 30% inhibition when tested against 100 nM Pacritinib at ATP concentrations equivalent to its Michaelis constant (K_m) [1].

Pacritinib: 2D and 3D Structure

The activity of Pacritinib is as follows:

IC₅₀ (JAK1 enzyme assay) = 1280 ± 370 nM
IC₅₀ (JAK2 enzyme assay) = 23 ± 6 nM
IC₅₀ (JAK2^V617F enzyme assay) = 19 nM
IC₅₀ (JAK3 enzyme assay) = 520 ± 110 nM
IC₅₀ (TYK2 enzyme assay) = 50 ± 6 nM
IC₅₀ (FLT3 enzyme assay) = 22 ± 6 nM
IC₅₀ (FLT3^D835Y enzyme assay) = 6 nM

1H NMR (Estimated) for Pacritinib

References:

1. Hart, S.; et. al. SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies. Leukemia 2011, 25(11), 1751-1759.

Drugs in Clinical Pipeline: Bafetinib

Bafetinib [(S)-N-(3-([4,5'-bipyrimidin]-2-ylamino)-4-methylphenyl)-4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)benzamide] is a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor which is 25 to 55 times more potent than Imatinib mesylate in vitro and at least 10 times more potent in vivo. It is a rationally developed tyrosine kinase inhibitor based on the chemical structure of Imatinib, with modifications added to improve binding and potency against Bcr-Abl kinase. Besides Abl, Bafetinib targets the Src family kinase Lyn, which has been associated with resistance to Imatinib in CML. Bafetinib shows potent and selective inhibitory activity against ABL (IC₅₀ = 11 nM) and Lyn (IC₅₀ = 26 nM) kinases. The IC₅₀ values of Bafetinib against wild-type Bcr-Abl in human erythroleukemia K562 cells and human embryonic kidney 293T cells are 11 and 22 nM, respectively, while the corresponding values for Imatinib are 280 and 1200 nM. Bafetinib is therefore 25 to 55 times more potent than imatinib in blocking Bcr-Abl autophosphorylation [1, 2]. 

The second-generation BCR-ABL inhibitor Bafetinib is known to inhibit most BCR-ABL mutants and LYN efficiently. Knowledge of its full target spectrum would provide the molecular basis for potential side effects or suggest novel therapeutic applications and possible combination therapies. Researchers have performed an unbiased chemical proteomics native target profile of Bafetinib in CML cells combined with functional assays using 272 recombinant kinases thereby identifying several new Bafetinib targets. These include the kinases ZAK, DDR1/2 and various ephrin receptors. The oxidoreductase NQO2, inhibited by both imatinib and nilotinib, is not a relevant target of Bafetinib. Overall, INNO-406 has an improved activity over imatinib but a slightly broader target profile than both imatinib and nilotinib. In contrast to dasatinib and bosutinib, Bafetinib does not inhibit all SRC kinases and most TEC family kinases and is therefore expected to elicit fewer side effects. Altogether, these properties may make Bafetinib a valuable component in the drug arsenal against Chronic Myeloid Leukemia (CML) [3].

Bafetinib inhibits 12 of the 13 most frequent Imatinib-resistant Bcr-Abl point mutations, but not a Thr315Ile mutation. A small fraction of Bafetinib crosses the blood-brain barrier, reaching brain concentrations adequate for suppression of Bcr-Abl+ cells. Data from a phase I clinical trial conducted in patients with Imatinib-resistant or -intolerant CML have confirmed that Bafetinib has clinical activity in this setting, inducing a major cytogenetic response in 19% of those patients in chronic phase. Currently, Bafetinib is being developed in two phase II clinical trials for patients with B-cell chronic lymphocytic leukemia and prostate cancer, and a trial is in progress for patients with brain tumors [4].

Bafetinib is being developed by CytRx under license from Nippon Shinyaku for treating Bcr-Abl+ leukemia's, including chronic myelogenous leukemia (CML) and Philadelphia+ acute lymphoblastic leukemia. 

The activity of Bafetinib is as follows:

IC₅₀ (ABL enzyme assay) = 11 nM

IC₅₀ (LYN enzyme assay) = 26 nM

IC₅₀ (ABL2 enzyme assay) = 9 nM

IC₅₀ (c-KIT enzyme assay) = 840 nM

IC₅₀ (c-KIT^V560G enzyme assay) = 51 nM

IC₅₀ (PDGFRα enzyme assay) = 56 nM

IC₅₀ (PDGFRα^D842V enzyme assay) = 1281 nM

IC₅₀ (PDGFRα^V561D enzyme assay) = 59 nM

Ref 3 gives IC₅₀ for ABL and LYN as 9 and 51 nM, respectively.

Common Name: Bafetinib

Synonyms: INNO-406; INNO406; INNO 406; NS-187; NS187; NS 187; CNS-9

IUPAC Name: (S)-N-(3-([4,5'-bipyrimidin]-2-ylamino)-4-methylphenyl)-4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)benzamide

CAS Number: 859212-16-1

SMILES:CC1=C(C=C(C=C1)NC(=O)C2=CC(=C(C=C2)CN3CCC(C3)N(C)C)C(F)(F)F)NC4=NC=C(C=N4)C5=CN=CN=C5

Mechanism of Action: Kinase Inhibitor; Dual-Kinase Inhibitor; ABL Kinase Inhibitor; LYN Kinase Inhibitor

Indication: Various Cancers; Treatment of Chronic Myeloid Leukemia

Development Stage: Phase II

Company: CytRx Corporation/Nippon Shinyaku Co

References:
1. Tomoko, N.; et. al. NS-187 (INNO-406), a Bcr-Abl/Lyn Dual Tyrosine Kinase Inhibitor. Anal Chem Insights 2007, 2, 93-106.
2. Asaki, T.; et. al. Design and synthesis of 3-substituted benzamide derivatives as Bcr-Abl kinase inhibitors. Bioorg Med Chem Lett 2006, 16(5), 1421-1425.
3. Rix, U.; et. al. A comprehensive target selectivity survey of the BCR-ABL kinase inhibitor INNO-406 by kinase profiling and chemical proteomics in chronic myeloid leukemia cells. Leukemia 2010, 24(1), 44-50.
4. Santos, F. P.; et. al. Bafetinib, a dual Bcr-Abl/Lyn tyrosine kinase inhibitor for the potential treatment of leukemia. Curr Opin Investig Drugs 2010, 11(12), 1450-1465.

Drugs in Clinical Pipeline: Cerdulatinib

Cerdulatinib [4-(cyclopropylamino)-2-({4-[4-(ethylsulfonyl)piperazin-1-yl]phenyl}amino) pyrimidine-5-carboxamide], is an orally active kinase inhibitor that demonstrates activity against spleen tyrosine kinase (SYK, IC₅₀ = 32 nM) and Janus kinase (JAK1, 2, 3 IC₅₀ = 12, 6, 8 nM, respectively) [1].

Dual inhibition of SYK and JAK represents such a strategy and may elicit several benefits relative to selective kinase inhibition, such as gaining control over a broader array of disease etiologies, reducing probability of selection for bypass disease mechanisms, and the potential that an overall lower level suppression of individual targets may be sufficient to modulate disease activity.

Cerdulatinib behaves like a multikinase inhibitor as in specificity assays it showed affinity towards other kinases also. It inhibited nearly 25 tested kinases with IC₅₀ less than 200 nM. Cerdulatinib blocks the B-cell receptor pathway via Syk and cytokine pathways via JAK 1, 3 and Tyk 2, hence it has a unique profile where it inhibits two validated tumor proliferation pathways that contribute to tumor cell growth and survival in certain hematologic malignancies. Moreover, Cerdulatinib has a favorable pharmacokinetic profile with a half-life of 14-18 hours that supports once-daily dosing. There parameters suggest that Cerdulatinib can be used in treatment of patients with genetically-defined hematologic cancers, as well as those who have failed therapy due to relapse or acquired mutations.

Cerdulatinib was discovered at Portola Pharmaceuticals. A Phase 1/2a study involving Cerdulatinib is ongoing in chronic lymphocytic leukemia (CLL) and B-cell non-Hodgkin lymphoma (NHL) patients. Results of in vitro studies suggest that the anti-tumor activity of Cerdulatinib is mediated by dual inhibition of Syk and JAK signaling pathways, and that Cerdulatinib may be a potent treatment for diffuse large B-cell lymphoma (DLBCL), an aggressive form of non-Hodgkin’s lymphoma (NHL). Cerdulatinib also has shown in vitro efficacy in ibrutinib-resistant chronic lymphocytic leukemia (CLL) and in DLBCL with certain mutations.

The activity of Cerdulatinib is as follows:

IC₅₀ (SYK enzyme assay) = 32 nM

IC₅₀ (JAK1 enzyme assay) = 12 nM

IC₅₀ (JAK2 enzyme assay) = 6 nM

IC₅₀ (JAK3 enzyme assay) = 8 nM

IC₅₀ (TYK2 enyme assay) =  0.5  nM

IC₅₀ (MST1 enyme assay) = 4  nM

IC₅₀ (ARK5 enyme assay) = 4  nM

IC₅₀ (MLK1 enyme assay) = 5  nM

IC₅₀ (Fms enyme assay) = 5  nM

IC₅₀ (AMPK enyme assay) = 6  nM

IC₅₀ (TBK1 enyme assay) = 10  nM

IC₅₀ (MARK1 enyme assay) = 10  nM

IC₅₀ (PAR1B-a enyme assay) = 13  nM

IC₅₀ (TSSK enyme assay) = 14  nM

IC₅₀ (MST2 enyme assay) = 15  nM

IC₅₀ (GCK enyme assay) = 18  nM

IC₅₀ (JNK3 enyme assay) = 18  nM

IC₅₀ (RSK2 enyme assay) = 20  nM

IC₅₀ (RSK4 enyme assay) = 28  nM

IC₅₀ (Chk1 enyme assay) = 42  nM

IC₅₀ (FLT4 enyme assay) = 51  nM

IC₅₀ (FLT3 enyme assay) = 90  nM

IC₅₀ (RET enyme assay) = 105  nM

IC₅₀ (ITK enyme assay) = 194  nM

Common Name: Cerdulatinib

Synonyms:  PRT2070; PRT-2070; PRT 2070; PRT-062070; PRT 062070; PRT062070

IUPAC Name: 4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino) pyrimidine-5-carboxamide

CAS Number: 1198300-79-6

Mechanism of Action: Kinase Inhibitor; Dual-Kinase Inhibitor; SYK Inhibitor; JAK Inhibitor

Indication: Various Cancers; Chronic Lymphocytic Leukemia; B-cell Non-Hodgkin Lymphoma

Development Stage: Phase II

Company: Portola Pharmaceuticals

In cellular assays Cerdulatinib demonstrated specific inhibitory activity against signaling pathways that use SYK and JAK1/3. Limited inhibition of JAK2 was observed, and Cerdulatinib did not inhibit phorbol 12-myristate 13-acetate-mediated signaling or activation in B and T cells nor T-cell antigen receptor-mediated signaling in T cells, providing evidence for selectivity of action. Potent antitumor activity was observed in a subset of B-cell lymphoma cell lines. After oral dosing, Cerdulatinib suppressed inflammation and autoantibody generation in a rat collagen-induced arthritis model and blocked B-cell activation and splenomegaly in a mouse model of chronic B-cell antigen receptor stimulation [1].      

References:
1. Coffey, G.; et. al. The novel kinase inhibitor PRT062070 (Cerdulatinib) demonstrates efficacy in models of autoimmunity and B-cell cancer. J Pharmacol Exp Ther 2014, 351(3), 538-548.  

Drugs in Clinical Pipeline: Refametinib

Refametinib [(R)-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide] is an orally available, potent, non-ATP-competitive and highly selective inhibitor of MEK1/2 (IC₅₀ MEK1, MEK2 = 19 nM, 47 nM). Refametinib-MEK complex structure reveals that Refametinib binds to an allosteric site adjacent to the Mg-ATP binding region and interacts extensively with ATP, the activation loop, and other surrounding protein residues through hydrogen bonding and hydrophobic interactions. Such a binding mode thus suggests a noncompetitive mechanism of inhibition of Refametinib against MEK1, which allows ATP binding but precludes binding to the substrate ERK, thus preventing ERK phosphorylation [1].

Refametinib significantly inhibited only MEK1/2 relative to 205 other kinases in a multikinase screen. MEK1 and MEK2 were inhibited 97% and 99%, respectively, when tested at 10 µM. Four other kinases (BRAF, BRAF V599E, COT, and RAF1) showed inhibition of greater than 90%; however, these used MEK1 in a cascade assay format and the inhibition in these assays is due to MEK1 inhibition rather than direct inhibition of the other kinases by Refametinib [1]. It was selected for clinical development because of its potency and favourable pharmacokinetic profile.

Refametinib was discovered at Ardea Biosciences. It has been licensed to Bayer since 2009 onwards. Refametinib is currently in a Phase 2 study in patients with hepatocellular carcinoma in combination with Sorafenib/Regorafenib and a Phase 1/Phase 2 study in patients with advanced pancreatic cancer in combination with Gemcitabine.

The activity of Refametinib is as follows:

IC₅₀ (MEK1 enzyme assay) = 19 nM

IC₅₀ (MEK2 enzyme assay) = 47 nM

Common Name: AMG 925

Synonyms:  BAY-86-9766; RDEA119; RDEA 119; BAY 86-9766

IUPAC Name: (R)-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide

CAS Number: 923032-37-5

Mechanism of Action: Kinase Inhibitor; Dual-Kinase Inhibitor; MEK1 Inhibitor; MEK2 Inhibitor

Indication: Various Cancers

Development Stage: Phase II

Company: Ardea Biosciences/Bayer

Studies of primary tumor samples and immortalized cancer cell lines have shown constitutive activation of the RAS-RAF-MEK-ERK pathway in several human tumors, including lung, colon, melanoma, thyroid, and pancreatic cancer. The mitogen-activated protein kinase pathway-also known as the RAS/RAF/MEK/extracellular signal-regulated kinase (ERK) pathway [MAP kinase (MAPK) pathway]-is a ubiquitous intracellular cascade that transduces signals from cell surface receptors to regulate numerous cytoplasmic and nuclear proteins involved in cellular proliferation, survival, differentiation, migration, and angiogenesis.  Overexpression of RAS, down-regulation of the natural inhibitors of the MAPK pathway, and overexpression of MEK and ERK are the mechanisms of MAPK pathway activation in cancers such as HCC. Moreover, ERK overexpression has been correlated with various disease progressions, thus making these as important targets for drug discovery. Within this pathway lies MEK for which there are two highly homologous genes expressed in humans (MEK1 and MEK2). MEK is downstream of BRAF in the RAS-RAF-MEK-ERK pathway and is critical for transducing signals to ERK. BRAF activating gene mutations are prevalent in melanoma and thyroid cancers.

In vivo, AMG 925 exhibits potent activity in xenograft models of melanoma, colon, and epidermal carcinoma. AMG 925 exhibits complete suppression of ERK phosphorylation at fully efficacious doses in mice. AMG 925 shows a tissue selectivity that reduces its potential for central nervous system-related side effects. Using pharmacokinetic and pharmacodynamic data, we show that maintaining adequate MEK inhibition throughout the dosing interval is likely more important than achieving high peak levels because greater efficacy was achieved with more frequent but lower dosing. Based on its longer half-life in humans than in mice, AMG 925 has the potential for use as a once- or twice-daily oral treatment for cancer [1].

Refametinib potently inhibited MEK activity as measured by phosphorylation of ERK1/2 across several human cancer cell lines of different tissue origins and BRAF mutational status with EC₅₀ values ranging from 2.5 to 15.8 nM. To assess the potential for brain penetration and activity, we compared the ability of Refametinib to inhibit pERK levels in the brain, lung, and tumor tissues of tumor-bearing mice and found at least that 76-fold lower plasma levels of Refametinib were required to inhibit 50% of the pERK level in tumor versus brain [1].

Refametinib exhibited potent antiproliferative activity in hepatocellular carcinoma (HCC) cell lines with half-maximal inhibitory concentration values ranging from 33 to 762 nM. Refametinib was strongly synergistic with sorafenib in suppressing tumor cell proliferation and inhibiting phosphorylation of the extracellular signal-regulated kinase (ERK). Refametinib prolonged survival in Hep3B xenografts, murine Hepa129 allografts, and MH3924A rat allografts. Additionally, tumor growth, ascites formation, and serum alpha-fetoprotein levels were reduced. Synergistic effects in combination with Sorafenib were shown in Huh-7, Hep3B xenografts, and MH3924A allografts. These results support the ongoing clinical development of Refametinib and Sorafenib in advanced HCC [2].

References:

1. Iverson, C.; et. al. RDEA119/BAY 869766: a potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancer. Cancer Res 2009, 69(17), 6839-6847.
2. Schmieder, R.; et. al. Allosteric MEK1/2 Inhibitor Refametinib (BAY 86-9766) in Combination with Sorafenib Exhibits Antitumor Activity in Preclinical Murine and Rat Models of Hepatocellular Carcinoma. Neoplasia 2013, 15(10), 1161-1171.

3. ClinicalTrials.gov Refametinib(BAY86-9766) in RAS Mutant Hepatocellular Carcinoma (HCC). NCT01915589 (retrieved 01-08-2015)

4. ClinicalTrials.gov BAY86-9766 Plus Gemcitabine Phase I Study in Asian. NCT01764828 (retrieved 01-08-2015)

5. ClinicalTrials.gov Refametinib (BAY86-9766) in Combination With Regorafenib (Stivarga, BAY73-4506) in Patients With Advanced or Metastatic Cancer. NCT02168777 (retrieved 01-08-2015)

Drugs in Clinical Pipeline: Gedatolisib

Gedatolisib [1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea] is an exceptionally potent, selective, ATP-competitive, and reversible dual Phosphoinositide 3-kinase (PI3K)/mTOR inhibitor. It is administered intravenously.

Gedatolisib suppressed phosphorylation of PI3K/mTOR effectors (e.g., Akt), and induced apoptosis in human tumor cell lines with elevated PI3K/mTOR signaling. MDA-MB-361 [breast; HER2+, PIK3CA mutant (E545K)] was particularly sensitive to this effect, with cleaved PARP, an apoptosis marker, induced by 30 nM of Gedatolisib PKI-587 at 4 hours.

In vitro, Gedatolisib potently inhibited class I PI3Ks (IC₅₀ PI3K-α = 0.4 nM, PI3K-β = 60 nM, PI3K-γ = 60 nM), PI3K-α mutants (IC₅₀ E545K = 0.6 nM, H1047R = 0.8 nM), and mTOR (IC₅₀ = 10 nM). Gedatolisib inhibited growth of 50 diverse human tumor cell lines at IC₅₀ values of less than 100 nM.

The activity of Gedatolisib is as follows:

IC₅₀ (PI3K-α enzyme assay) = 0.4 nM

IC₅₀ (PI3K-β enzyme assay) = 60 nM

IC₅₀ (PI3K-γ enzyme assay) = 60 nM

IC₅₀ (mTOR enzyme assay) = 10 nM

Common Name: Gedatolisib

Synonyms:  PKI-587; PF-05212384; PF05212384; PF 05212384; PF5212384

IUPAC Name: 1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea

CAS Number: 1197160-78-3

SMILES:O=C(NC1=CC=C(C2=NC(N3CCOCC3)=NC(N4CCOCC4)=N2)C=C1)NC5=CC=C(C(N6CCC(N(C)C)CC6)=O)C=C5

Mechanism of Action: Kinase Inhibitor; PI3K Inhibitor; mTOR Inhibitor; Dual-Kinase Inhibitor

Indication: Various Cancers; Treatment of Solid Tumors

Development Stage: Phase I

Company: Pfizer

Class 1 phosphoinositide 3-kinases (PI3K) play a key role in the biology of human cancer. The gene encoding the PI3K-α isoform (PIK3CA) is amplified or mutated in a wide range of cancers. Aberrantly elevated PI3K/Akt/mTOR pathway signaling has been implicated in poor prognosis and survival in patients with lymphatic, breast, prostate, lung, glioblastoma, melanoma, colon, and ovarian cancers. In addition, PI3K/Akt/mTOR pathway activation contributes to resistance of cancer cells to both targeted anticancer therapies and conventional cytotoxic agents. An effective inhibitor of the PI3K/Akt/mTOR pathway could prevent cancer cell proliferation and induce programmed cell death [1].

Gedatolisib, a potent pan–class I phosphoinositide 3-kinase (PI3K)/mTOR inhibitor, showed single-agent efficacy in multiple preclinical tumor models. Tumor regression was observed in several models. This effect was most pronounced against MDA-MB-361 (breast), which has elevated HER2 levels and mutant PI3K-α. Preclinical data suggest utility of PKI-587 in the treatment of cancers with elevated PI3K/mTOR signaling, including those resistant to agents that target HER2 or epidermal growth factor (EGF) receptors (EGFR).PKI-587 efficacy was enhanced when combined with a MEK1,2 kinase inhibitor (PD0325901), or irinotecan in a colon tumor model (HCT116) with mutant K-Ras. PKI-587 showed single-agent efficacy against a non–small cell lung cancer model (H1975) with mutant EGFR (L858R/T790M), and this activity was also enhanced when combined with the irreversible HER2 kinase inhibitor, HKI-272 [1].

Gedatolisib showed single-agent efficacy in both xenograft and orthotopic versions of the H1975 [NSCLC; EGFR (L858R/T790M)] model. In H1975 xenografts, continuous dosing of PKI-587 (at >5 mg/kg) caused early time point tumor regression. In the H1975 orthotopic model, 25 mg/kg PKI-587 (weekly) kept (9 of 10) treated mice alive, whereas all control mice (10 of 10) were dead by day 40. This suggests that PKI-587 could be used against lung tumors that have acquired resistance to EGFR inhibitors such as Iressa or Tarceva.

Phase I Study in Patients with Advanced Cancer

The part 1 of this open-label phase I study was designed to estimate the maximum-tolerated dose (MTD) in patients with nonselected solid tumors, using a modified continual reassessment method to guide dose escalation. Objectives of part 2 were MTD confirmation and assessment of preliminary activity in patients with selected tumor types and PI3K pathway dysregulation [3].

Methodology and Findings

Seventy-seven of the 78 enrolled patients received treatment. The MTD for Gedatolisib, administered intravenously once weekly, was estimated to be 154 mg. The most common treatment-related adverse events (AE) were mucosal inflammation/stomatitis (58.4%), nausea (42.9%), hyperglycemia (26%), decreased appetite (24.7%), fatigue (24.7%), and vomiting (24.7%). The majority of patients treated at the MTD experienced only grade 1 treatment-related AEs. Grade 3 treatment-related AEs occurred in 23.8% of patients at the MTD. No treatment-related grade 4-5 AEs were reported at any dose level. Antitumor activity was noted in this heavily pretreated patient population, with two partial responses (PR) and an unconfirmed PR. Eight patients had long-lasting stable disease (greater than 6 months). Pharmacokinetic analyses showed a biphasic concentration-time profile for Gedatolisib (half-life, 30-37 hours after multiple dosing). Gedatolisib inhibited downstream effectors of the PI3K pathway in paired tumor biopsies.

Results

Gedatolisib has potential to advance into further clinical development for patients with advanced solid malignancies.

References:

1. Mallon, R.; et. al. Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitor. Clin Cancer Res 2011, 17(10), 3193-3203.
2. Venkatesan, A. M.; et. al. Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5'-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor. J Med Chem 2010, 53(6), 2636-2645. (synthesis)
3. Shapiro, G. I.; et. al. First-in-Human Study of PF-05212384 (PKI-587), a Small-Molecule, Intravenous, Dual Inhibitor of PI3K and mTOR in Patients with Advanced Cancer. Clin Cancer Res 2015, 21(8), 1888-1895.
4. ClinicalTrials.gov  Study of PF-05212384 (Also Known as PKI-587) Administered Intravenously To Subjects With Solid Tumors (B2151001). NCT00940498 (retrieved 19-05-2015)
5. ClinicalTrials.gov Investigation Of The Metabolism, And Excretion Of [14c]-PF-05212384 In Healthy Male Volunteers. NCT02142920 (retrieved 19-05-2015)
6. ClinicalTrials.gov A Study Of PF-05212384 In Combination With Other Anti-Tumor Agents. NCT01920061 (retrieved 19-05-2015)