Structure-guided discovery of 2-aryl/pyridin-2-yl-1H-indole derivatives as potent and selective hepsin inhibitors.

Hepsin, a type II transmembrane serine protease, is upregulated in prostate cancer and known to be involved in the progression of metastasis. Here we report a structure-guided approach, which resulted in the discovery of 2-aryl/pyridin-2-yl-1H-indole derivatives as potent and selective inhibitors of hepsin. Potent and selective inhibition of hepsin by compound 8 is likely due to interactions of the amidine group at the S1 site with the cyclohexyl ring from the 2-aryl group projecting towards the S1' site and the tert-hydroxyl group interacting with His57 side-chain as revealed by X-ray crystallography. Compounds 8 and 10, showed Ki of 0.1 µM for hepsin, and exhibited inhibition of invasion and migration of hepsin-overexpressing cell line. Compounds described here could serve as useful tool reagents to investigate the role of hepsin as a potential therapeutic target in cancer.

Discovery of CA-4948, an Orally Bioavailable IRAK4 Inhibitor for Treatment of Hematologic Malignancies.

Small molecule potent IRAK4 inhibitors from a novel bicyclic heterocycle class were designed and synthesized based on hits identified from Aurigene's compound library. The advanced lead compound, CA-4948, demonstrated good cellular activity in ABC DLBCL and AML cell lines. Inhibition of TLR signaling leading to decreased IL-6 levels was also observed in whole blood assays. CA-4948 demonstrated moderate to high selectivity in a panel of 329 kinases as well as exhibited desirable ADME and PK profiles including good oral bioavailability in mice, rat, and dog and showed >90% tumor growth inhibition in relevant tumor models with excellent correlation with in vivo PD modulation. CA-4948 was well tolerated in toxicity studies in both mouse and dog at efficacious exposure. The overall profile of CA-4948 prompted us to select it as a clinical candidate for evaluation in patients with relapsed or refractory hematologic malignancies including non-Hodgkin lymphoma and acute myeloid leukemia.

Discovery of Pyridyl Bis(oxy)dibenzimidamide Derivatives as Selective Matriptase Inhibitors.

Matriptase belongs to trypsin-like serine proteases involved in matrix remodeling/degradation, growth regulation, survival, motility, and cell morphogenesis. Herein, we report a structure-based approach, which led to the discovery of sulfonamide and amide derivatives of pyridyl bis(oxy)benzamidine as potent and selective matriptase inhibitors. Co-crystal structures of selected compounds in complex with matriptase supported compound designing. Additionally, WaterMap analyses indicated the possibility of occupying a distinct pocket within the catalytic domain, exploration of which resulted in >100-fold improvement in potency. Co-crystal structure of 10 with matriptase revealed critical interactions leading to potent target inhibition and selectivity against other serine proteases.