title: Rational evolution of a novel type of potent and selective proviral integration site in Moloney murine leukemia virus kinase 1 (PIM1) inhibitor from a screening-hit compound.
abstract: Serine/threonine kinase PIM1 is an emerging therapeutic target for hematopoietic and prostate cancer therapy. To develop a novel PIM1 inhibitor, we focused on 1, a metabolically labile, nonselective kinase inhibitor discovered in our previous screening study. We adopted a rational optimization strategy based mainly on structural information for the PIM1-1 complex to improve the potency and selectivity. This approach afforded the potent and metabolically stable PIM1-selective inhibitor 14, which shows only a marginal increase in molecular weight compared with 1 but has a significantly decreased cLogP. The validity of our design concept was confirmed by X-ray structure analysis. In a cellular study, 14 potently inhibited the growth of human leukemia cell line MV4-11 but had a negligible effect on the growth of WI-38 (surrogate for general toxicity). These results demonstrate the effectiveness of our design strategy for evolving the screening-hit compound 1 into a novel type of PIM1 inhibitor, 14.
authors.affiliation: Open Innovation Center for Drug Discovery, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Nakano
authors.forename: Nae
authors.initials: N
authors.lastname: Saito
authors.forename: Lorien
authors.initials: L
authors.lastname: Parker
authors.forename: Yukio
authors.initials: Y
authors.lastname: Tada
authors.forename: Masanao
authors.initials: M
authors.lastname: Abe
authors.forename: Keiko
authors.initials: K
authors.lastname: Tsuganezawa
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Akiko
authors.initials: A
authors.lastname: Tanaka
authors.forename: Hirotatsu
authors.initials: H
authors.lastname: Kojima
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Okabe
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nagano
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D004354:Drug Screening Assays, Antitumor; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007938:Leukemia; D008958:Models, Molecular; D015394:Molecular Structure; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001372:Aza Compounds; D001572:Benzofurans; D007211:Indoles; D051573:Proto-Oncogene Proteins c-pim-1