Synthesis and evaluation of substituted hexahydronaphthalenes as novel inhibitors of the Mcl-1/BimBH3 interaction.
Mcl-1, an anti-apoptotic member of the Bcl-2 protein family, is overexpressed in a broad range of human cancers and plays a critical role in conferring resistance to chemotherapy. In the course of screening a natural product-like library of sesquiterpenoid analogs, we identified substituted hexahydronaphthalenes that showed activity against the Mcl-1/BimBH3 interaction in vitro. Here, we describe the synthesis of a small library of analogs and their biological evaluation. The most potent inhibitor in the series (19) exhibits an IC(50) of 8.3 μM by ELISA and disrupts the interaction between endogenously expressed Mcl-1 and Bim in cultured MDA-MB-468 breast cancer cells.
Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Young B
YB
Kim
Maria E
ME
Balasis
Kenichiro
K
Doi
Norbert
N
Berndt
Courtney
C
DuBoulay
Chih-Chi Andrew
CC
Hu
Wayne
W
Guida
Hong-Gang
HG
Wang
Saïd M
SM
Sebti
Juan R
JR
Del Valle
D000970:Antineoplastic Agents / Q000737:chemistry; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009281:Naphthalenes; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2