The in silico construction of a PDGFRβ kinase homology model and ensuing medicinal chemistry guided by molecular modeling, led to the identification of potent, small molecule inhibitors of PDGFR. Subsequent exploration of structure-activity relationships (SAR) led to the incorporation of a constrained secondary amine to enhance selectivity. Further refinements led to the integration of a fluorine substituted piperidine, which resulted in significant reduction of P-glycoprotein (Pgp) mediated efflux and improved bioavailability. Compound 28 displayed oral exposure in rodents and had a pronounced effect in a pharmacokinetic-pharmacodynamic (PKPD) assay.

The epidermal growth factor receptor (EGFR) family consists of four receptor tyrosine kinases, two of which that can function as important human oncogenes making them attractive as potential therapeutic targets. The growth factor receptor tyrosine kinases EGFR (ErbB1) and Her2 (ErbB2), in particular, perform a major role in controlling cell growth and differentiation. ErbB2 is over -expressed in multiple human tumors of epithelial origin; most notably in breast, ovarian and stomach cancers. Overexpression of ErbB2 in many of theses cancers is associated with poor clinical outcome in human patients. The critical role of ErbB2 in growth factor signaling and the clinical efficacy data with targeted ErbB2 agents (e.g., trastuzumab, lapatinib) confirms inhibition of ErbB2 as an attractive target for tumor growth inhibition. ARRY-380 is an orally active, selective, small molecule inhibitor of ErbB2. Its activity (IC50) against ErbB2 enzyme is 14 nM and it inhibits the phosphorylation of ErbB2 in BT474 cells in culture with an IC 50 of 21 nM. ARRY-380 also potently inhibits phosphorylation of AKT, induces apoptosis and inhibits growth of BT474 cells in vitro. This compound has excellent in vivo and in vitro ADME properties, including dose-proportional exposure in rodents and in primates and an excellent metabolic profile. In vivo efficacy of ARRY-380 has been tested in numerous tumor xenograft models. Marked tumor growth inhibition has been demonstrated in NIH-3T3 cells stably transfected with constitutively active ErbB2 kinase (3T3-rErbB2), NCI-N87 human gastric carcinoma, BT-474 human breast carcinoma and SK-O-V3 human ovarian adenocarcinoma. For the in vivo tumor studies, female nude mice were inoculated subcutaneously in the flank with tumor cells or cell fragments. Tumor size was measured at regular intervals for up to 21 days. Animals received oral doses of ARRY-380 ranging from 25 to 200 mg/kg/d for 21 days. ARRY-380 showed significant dose-related tumor growth inhibition (up to 96%) and significant regressions in the xenograft models evaluated. The inhibition of pErbB2 was measured in the 3T3-rErbB2 tumors. Consistent with the mechanism of action of ARRY-380, tumor growth inhibition correlated with decreased pErbB2 levels (92% inhibition at a dose of 50 mg/kg) in tumors obtained from the in vivo growth inhibition studies. In BT474 xenograft tumors treated with ARRY-380, inhibition of pErbB2 and of downstream signaling targets, AKT and ERK, has been demonstrated. Based on its superior preclinical activity and tolerability and excellent pharmacokinetic profile, ARRY-380 has entered Phase I studies in patients with solid tumors. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1795.