Abstract A130: Fragment-based discovery and optimization of Rho kinase inhibitors.

Abstract

Abstract Using high concentration biochemical assays and fragment-based screening, we designed and optimized a novel class of Rho-kinase inhibitors. Ligand Efficiency (LE) was employed to assess the binding potential of the fragments and to guide the optimization process. In addition, molecular modeling was used to aide the design of potent inhibitors. A series of fragments as hinge binders were designed and synthesized, and screened using high concentration biochemical assays. Both the spacer length and isomeric tail molecules played key roles in both activity and selectivity. Structure activity relationship studies led to optimization of fragments that yielded potent and selective ROCK 1 and ROCK 2 inhibitors. For instance, compound 24 was highly potent and selective for ROCK 2 (IC50 = 100 nM) over ROCK 1 (IC50 = 1690 nM) whereas compound 18 was potent and selective for ROCK 1 (IC50 = 460 nM) over ROCK 2 (IC50 = 700nM). Compound 24 but not its inactive stereoisomer 23, and compound 18 but not its inactive analog 11 inhibited the phosphorylation of Rho Kinase substrates in intact human cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A130.