Tim Heffron

Discovery of (Thienopyrimidin-2-yl)aminopyrimidines as Potent, Selective, and Orally Available Pan-PI3-Kinase and Dual Pan-PI3-Kinase/mTOR Inhibitors for the Treatment of Cancer.

The PI3K/AKT/mTOR pathway has been shown to play an important role in cancer. Starting with compounds 1 and 2 (GDC-0941) as templates, (thienopyrimidin-2-yl)aminopyrimidines were discovered as potent inhibitors of PI3K or both PI3K and mTOR. Structural information derived from PI3K gamma-ligand cocrystal structures of 1 and 2 were used to design inhibitors that maintained potency for PI3K yet improved metabolic stability and oral bioavailability relative to 1. The addition of a single methyl group to the optimized 5 resulted in 21, which had significantly reduced potency for mTOR. The lead compounds 5 (GNE-493) and 21 (GNE-490) have good pharmacokinetic (PK) parameters, are highly selective, demonstrate knock down of pathway markers in vivo, and are efficacious in xenograft models where the PI3K pathway is deregulated. Both compounds were compared in a PI3K alpha mutated MCF7.1 xenograft model and were found to have equivalent efficacy when normalized for exposure.

Abstract LB-309: Non-covalent wild-type-sparing inhibitors of EGFR T790M .

Non-small cell lung cancers (NSCLC) with activating EGFR mutations respond well to the selective EGFR kinase inhibitors, gefitinib and erlotinib. Despite initial responses, most patients relapse within one year due to acquired resistance. Approximately half of these cases are associated with a secondary EGFR kinase domain mutation, T790M–the “gatekeeper” mutation. Irreversible EGFR kinase inhibitors have demonstrated pre-clinical efficacy toward EGFR T790M and have been undergoing clinical evaluation. However, the current irreversible inhibitors have yet to yield clinical activity in this setting, possibly due to dose-limiting toxicities. In a cancer cell line screening effort, we identified the PKC inhibitor, Go6976, a staurosporine derivative, as an inhibitor of EGFR mutant-driven NSCLC cells. Further analysis revealed that Go6976 potently suppresses both autophosphorylation and ligand-induced phosphorylation of EGFR mutants including T790M. Among some structurally-related bis-indole-based compounds currently undergoing clinical testing, PKC412, a FLT3 kinase inhibitor, demonstrated -100 fold greater potency against EGFR T790M than Go6976. Interestingly, while irreversible inhibitors are less potent against EGFR T790M than either EGFR WT or EGFR activating mutants, the bis-indole-based compounds show substantially greater potency against EGFR T790M, effectively sparing WT EGFR. Our findings suggest that this class of reversible inhibitors may be more effective and better tolerated than irreversible inhibitors to overcome EGFR T790M-mediated acquired drug resistance in NSCLC. Citation Format: Ho-June Lee, Gabriele Schaefer, Tim Heffron, Shiva Malek, Mark Merchant, Robert L. Yauch, Valentina Pirazzoli, Katerina Politi, Jeff Settleman. Non-covalent wild-type-sparing inhibitors of EGFR T790M . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-309. doi:10.1158/1538-7445.AM2013-LB-309

Abstract C201: A novel potent and selective inhibitor of PI3K/mTOR, GDC‐0980, currently in phase I clinical trials

Introduction: The phosphoinositide‐3 kinase (PI3K)/Akt signaling pathway is deregulated in a wide variety of cancers. Somatic activating mutations and amplifications in PI3K are common in multiple cancers including breast, colon, and lung cancer. PTEN, a phosphatase that converts PIP3 to PIP2 and thus has an opposing function to PI3K, is a commonly mutated tumor suppressor in multiple cancers including prostate and glioblastoma. Alterations of this pathway have been implicated in tumor initiation, progression, survival, angiogenesis, and metastasis. PI3K/Akt pathway activation has also been implicated in therapeutic resistance. Thus PI3K is considered to be a promising therapeutic target for cancer. Summary of Results: Medicinal chemistry efforts resulted in the discovery of GDC‐0980, a selective, orally bioavailable inhibitor of PI3 Kinase and mTOR kinase with promising pharmacokinetic and pharmaceutical properties. Here we report the first pre‐clinical profile of GDC‐0980. This compound is a potent ATP‐competitive Class I PI3 kinase inhibitor with an IC50 of 4.8 nM against the PI3K p110apha subunit, 26.8 nM p110beta, 6.7 nM p110delta, 13.8 nM p110gamma, and an mTOR Kiapp of 17.3 nM. GDC‐0980 demonstrates selectivity against a large panel of protein kinases as well as selectivity over PIK family kinases including Class II, Class III, and DNA‐PK. GDC‐0980 inhibits the PI3K signaling pathway in vitro causing a reversible G1 cell cycle arrest, and apoptosis induction in a subset of tumor cell lines. Levels of signaling pathway markers such as phosphorylated AKT (pAKT), PRAS40 (pPRAS40), and S6 (pS6) are rapidly and dramatically reduced following exposure of cells to GDC‐0980. Oral dosing of GDC‐0980 potently inhibits tumor growth in xenograft models including those mutated in PI3K and PTEN, and elicits an exposure‐related concomitant decrease in PD biomarkers. Conclusion: These preclinical data provide compelling evidence in support of GDC‐0980 as a clinical candidate, and Phase I studies are ongoing. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C201.

Abstract 2787: Discovery of GDC-0980, a selective PI3K/mTOR inhibitor in clinical trials

PI3 Kinase and mTOR have been identified as promising targets for the treatment of cancer. These enzymes participate in related, but not redundant, signaling networks to transmit cellular growth and survival signals, which are hallmarks of tumor growth. An interest in targeting both of these two important points along this critical signaling pathway, and the ability to leverage the high degree of structural similarity in the active sites of PI3K and mTOR kinase, has resulted in the discovery of GDC-0980 as a Class I PI3K and mTOR kinase inhibitor for oncology indications. The structure, efficacy, and medicinal chemistry behind the discovery of this compound is described. Beginning with the morpholin-4-yl-thieno[3,2-d]pyrimidine core of the Class I PI3K inhibitor GDC-0941, structural substitutions were made external to the core that added mTOR potency, improved the metabolic stability in vitro and in vivo, and lowered the plasma protein binding of the scaffold. Homology models of mTOR using PI3Kγ structures with bound inhibitors provided hypotheses for increasing mTOR potency relative to previous compounds. The solubility of the modified compounds was improved through the addition of polar functionality in the solvent exposed region of the scaffold, resulting in GDC-0980. GDC-0980 is potent across Class I isoforms with IC509s of 5, 27, 7, and 14 nM for PI3Kα, β, Δ, and γ, and inhibits mTOR with a Ki of 17 nM. The compound is highly selective versus a large panel of kinases including others in the PIK family. Based on the excellent PK profile, linear increase in exposure, strong potency in a broad range of cancer cells, and high free fraction, GDC-0980 is efficacious in animal models of cancer when dosed orally at low doses. Furthermore, this compound is efficacious when dosed intermittently as well as on a daily schedule. These preclinical data provide compelling support for GDC-0980 as a clinical candidate, and early stage clinical trials are underway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2787. doi:10.1158/1538-7445.AM2011-2787