| Literature DB >> 27096050 |
Victor J Cee1, Frank Chavez1, Bradley Herberich1, Brian A Lanman1, Liping H Pettus1, Anthony B Reed1, Bin Wu1, Ryan P Wurz1, Kristin L Andrews1, Jie Chen1, Dean Hickman1, Jimmy Laszlo1, Matthew R Lee1, Nadia Guerrero1, Bethany K Mattson1, Yen Nguyen1, Christopher Mohr1, Karen Rex1, Christine E Sastri1, Paul Wang1, Qiong Wu1, Tian Wu1, Yang Xu1, Yihong Zhou1, Jeffrey T Winston1, J Russell Lipford1, Andrew S Tasker1, Hui-Ling Wang1.
Abstract
The identification of Pim-1/2 kinase overexpression in B-cell malignancies suggests that Pim kinase inhibitors will have utility in the treatment of lymphoma, leukemia, and multiple myeloma. Starting from a moderately potent quinoxaline-dihydropyrrolopiperidinone lead, we recognized the potential for macrocyclization and developed a series of 13-membered macrocycles. The structure-activity relationships of the macrocyclic linker were systematically explored, leading to the identification of 9c as a potent, subnanomolar inhibitor of Pim-1 and -2. This molecule also potently inhibited Pim kinase activity in KMS-12-BM, a multiple myeloma cell line with relatively high endogenous levels of Pim-1/2, both in vitro (pBAD IC50 = 25 nM) and in vivo (pBAD EC50 = 30 nM, unbound), and a 100 mg/kg daily dose was found to completely arrest the growth of KMS-12-BM xenografts in mice.Entities:
Keywords: KMS-12-BM; Pim kinase inhibitor; macrocycle; multiple myeloma
Year: 2016 PMID： 27096050 PMCID： PMC4834646 DOI： 10.1021/acsmedchemlett.5b00403
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345