Rationally simplified bistramide analog reversibly targets actin polymerization and inhibits cancer progression in vitro and in vivo.
We describe structure-based design and chemical synthesis of a simplified analog of bistramide A, which potently and reversibly binds monomeric actin with a K(d) of 9.0 nM, depolymerizes filamentous actin in vitro and in A549 (nonsmall cell lung cancer) cells, inhibits growth of cancer cell lines in vitro at submicromolar concentrations, and significantly suppresses proliferation of A549 cells in a nude mice tumor xenograft model in terms of both tumor growth delay and average tumor volume. This study provides a conceptual framework for the design and development of new antiproliferative compounds that target cytoskeletal organization of cancer cells in vivo by a combination of reversible G-actin binding and effective F-actin severing.
Rizvi
Syed Alipayam
SA
University of Chicago, Department of Chemistry, Chicago, Illinois 60637, USA.
Liu
Song
S
Chen
Zhonglei
Z
Skau
Colleen
C
Pytynia
Matthew
M
Kovar
David R
DR
Chmura
Steven J
SJ
Kozmin
Sergey A
SA
D000081:Acetamides / Q000737:chemistry*; D000199:Actins / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015195:Drug Design; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000378:metabolism*; D011714:Pyrans / Q000737:chemistry*; D013141:Spiro Compounds / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
D000081:Acetamides; D000199:Actins; D000970:Antineoplastic Agents; D011714:Pyrans; D013141:Spiro Compounds; C059975:bistratene A