Portal de Periódicos da CAPES

The discovery and optimization of aminooxadiazoles as potent Pim kinase inhibitors

2015; Elsevier BV; Volume: 25; Issue: 4 Linguagem: Inglês

10.1016/j.bmcl.2014.12.067

1464-3405

Ryan P. Wurz, Liping H. Pettus, Claire Jackson, Bin Wu, Huiling Wang, Brad Herberich, Victor J. Cee, Brian A. Lanman, Anthony B. Reed, Frank Chavez, Thomas Nixey, Jimmy Laszlo, Paul Wang, Yen Nguyen, Christine Sastri, Nadia Guerrero, Jeff Winston, J. Russell Lipford, Matthew R. Lee, Kristin L. Andrews, Christopher Mohr, Yang Xu, Yihong Zhou, Darren L. Reid, Andrew S. Tasker,

Peptidase Inhibition and Analysis

High levels of Pim expression have been implicated in several hematopoietic and solid tumor cancers. These findings suggest that inhibition of Pim signaling by a small molecule Pim-1,2 inhibitor could provide patients with therapeutic benefit. Herein, we describe our progress towards this goal starting from the highly Pim-selective indole–thiadiazole compound (1), which was derived from a nonselective hit identified in a high throughput screening campaign. Optimization of this compound's potency and its pharmacokinetic properties resulted in the discovery of compound 29. Cyclopropane 29 was found to exhibit excellent enzymatic potency on the Pim-1 and Pim-2 isoforms (Ki values of 0.55 nM and 0.28 nM, respectively), and found to inhibit the phosphorylation of BAD in the Pim-overexpressing KMS-12 cell line (IC50 = 150 nM). This compound had moderate clearance and bioavailability in rat (CL = 2.42 L/kg/h; %F = 24) and exhibited a dose-dependent inhibition of p-BAD in KMS-12 tumor pharmacodynamic (PD) model with an EC50 value of 6.74 μM (18 μg/mL) when dosed at 10, 30, 100 and 200 mg/kg po in mice.