Discovery and Optimization of Quinazolinone-pyrrolopyrrolones as Potent and Orally Bioavailable Pan-Pim Kinase Inhibitors

The
high expression of proviral insertion site of Moloney murine leukemia
virus kinases (Pim-1, -2, and -3) in cancers, particularly the hematopoietic
malignancies, is believed to play a role in promoting cell survival
and proliferation while suppressing apoptosis. The three isoforms
of Pim protein appear largely redundant in their oncogenic functions.
Thus, a pan-Pim kinase inhibitor is highly desirable. However, cell
active pan-Pim inhibitors have proven difficult to develop because
Pim-2 has a low Km for ATP and therefore
requires a very potent inhibitor to effectively block the kinase activity
at cellular ATP concentrations. Herein, we report a series of quinazolinone-pyrrolopyrrolones
as potent and selective pan-Pim inhibitors. In particular, compound 17 is orally efficacious in a mouse xenograft model (KMS-12
BM) of multiple myeloma, with 93% tumor growth inhibition at 50 mg/kg
QD upon oral dosing.