Abstract 731: SRI-28731, a highly potent and selective MAP4K4 (HGK) inhibitor for cancer therapy

Abstract

Abstract MAP4K4, a Ser/Thr kinase, was identified as an important pro-migratory kinase in an siRNA screen, targeting 5,234 human genes for modulators of tumor cell motility. MAP4K4 siRNA potently suppressed cell invasion and migration of multiple cancer cell lines, indicating a broad role in cell motility. There are no drugs in the clinic that are known to specifically target MAP4K4 for cancer therapy. We have successfully developed an orally active, highly effective and selective MAP4K4 inhibitor (SRI-28731) with potent in vitro and in vivo anticancer activity. SRI-28731 is more potent than Paclitaxel (Taxol) against most of the breast cancer cell lines tested. SRI-28731 exhibits more potent activities against triple negative (MDA-MB-231, BT549 and Hs578T) than estrogen-dependent (T47D and MCF-7) breast cancer cell lines, and its potency is positively correlated with MAP4K4 expression in cancer cell lines. SRI-28731 is also more potent than Docetaxel against both androgen-dependent (LNCaP) and -independent (PC-3 and DU-145) prostate cancer cell lines. In vitro mechanistic studies showed that SRI-28731 induced apoptosis and a time-dependent M phase arrest. Treatment with SRI-28731 (12.5, 25 and 50 mg/kg/day) caused a significant dose-dependent growth reduction of PC-3 tumors (30%, 61% and 88% growth inhibition, respectively), while Docetaxel at its MTD (7.5 mg/kg; Q3Dx2) produced only 10-15% growth inhibition. At the end of PC-3 tumor xenograft studies, we conducted an ex vivo invasion assay using PC-3 tumor cells isolated from tumor-bearing mice. SRI-28731 significantly reduced ex vivo tumor cell invasion by ∼80%. Pharmacokinetic studies showed that SRI-28731 could be detected in plasma up to 8 hours after oral dosing, and drug plasma concentrations remained above the IC50 values needed to inhibit prostate or breast cancer proliferation. To quantitatively define the kinase selectivity of SRI-28731, we tested the interaction of SRI-28731 with 456 kinase protein kinases (KINOMEscan), followed by in vitro pharmacology studies. Our data indicated that SRI-28731 is a highly selective Type-II MAP4K4 inhibitor. Type II kinase inhibitors bind to both the ATP site and an adjacent hydrophobic site exposed in the non-activated kinase state. Generally, type II inhibitors show higher selectivity for targets, and act primarily by locking the equilibrium switch between conformational states in a way that prevents kinase activation, rather than directly inhibiting it. Elevated MAP4K4 expression is strongly associated with higher rate of metastasis, and is regarded as an independent predictor of overall survival in cancer patients. Since MAP4K4 is overexpressed in many human cancer cell lines but is undetectable in non-transformed epithelial cells, targeting MAP4K4 may provide effective anti-metastatic therapy with limited side effects on normal tissues. Citation Format: Chih-Tsung Chang, Jaehyeon Park, Wei Zhou, Xiaohe Liu, Barbara Sato, Dominic Dinh, Anna Furimsky, Lucia Beviglia, Lidia Sambucetti, Ling Jong. SRI-28731, a highly potent and selective MAP4K4 (HGK) inhibitor for cancer therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 731. doi:10.1158/1538-7445.AM2014-731