Hongbo Zeng

Discovery of novel imidazo[1,2-a]pyrazin-8-amines as Brk/PTK6 inhibitors.

A series of substituted imidazo[1,2-a]pyrazin-8-amines were discovered as novel breast tumor kinase (Brk)/protein tyrosine kinase 6 (PTK6) inhibitors. Tool compounds with low-nanomolar Brk inhibition activity, high selectivity towards other kinases and desirable DMPK properties were achieved to enable the exploration of Brk as an oncology target.

The Discovery of 3-((4-Chloro-3-methoxyphenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide, a Highly Ligand Efficient and Efficacious Janus Kinase 1 Selective Inhibitor with Favorable Pharmacokinetic Properties

The discovery of a potent selective low dose Janus kinase 1 (JAK1) inhibitor suitable for clinical evaluation is described. As part of an overall goal to minimize dose, we pursued a medicinal chemistry strategy focused on optimization of key parameters that influence dose size, including lowering human Clint and increasing intrinsic potency, bioavailability, and solubility. To impact these multiple parameters simultaneously, we used lipophilic ligand efficiency as a key metric to track changes in the physicochemical properties of our analogs, which led to improvements in overall compound quality. In parallel, structural information guided advancements in JAK1 selectivity by informing on new vector space, which enabled the discovery of a unique key amino acid difference between JAK1 (Glu966) and JAK2 (Asp939). This difference was exploited to consistently produce analogs with the best balance of JAK1 selectivity, efficacy, and projected human dose, ultimately culminating in the discovery of compound 28.

Abstract 1945: Inhibition of PTK6 kinase activity reduces proliferation and migration of tumor cells

Protein kinase 6 (PTK6) is a member of the Frk family of non-receptor tyrosine kinase that is overexpressed in several types of cancers with the highest overexpression observed in breast tumors. PTK6 shows sequence homology to the src tyrosine kinase family. Its functional domains, including a SH3, a SH2 and a kinase domain, are arranged similarly with src family kinases although PTK6 lacks a myristoylation domain. We have identified a potent small molecule PTK6 kinase inhibitor from kinase cross screens that inhibits PTK6 autophosphorylation and phosphorylation of its substrate Sam68, a member of the KH domain containing RNA binding proteins. In cell culture, the compound inhibited proliferation, soft agar growth and migration of tumor cells. The compound inhibited soft agar growth of breast tumor cells more potently than dasatinib. A specific PTK6 kinase inhibitor may provide a novel approach to inhibit the growth of selected tumors, sensitize the response of the tumor cells to other chemotherapeutics and prevent/inhibit metastasis of cancer in a wide range of cancer patients. 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 1945. doi:10.1158/1538-7445.AM2011-1945