BACKGROUND: The Hsp90s contain a conserved pocket that binds ATP/ADP and plays an important role in the regulation of chaperone function. Occupancy of this pocket by several natural products (geldanamycin (GM) and radicicol) alters Hsp90 function and results in the degradation of a subset of proteins (i.e. steroid receptors, Her2, Raf). We have used the structural features of this pocket to design a small molecule inhibitor of Hsp90. RESULTS: The designed small molecule PU3 competes with GM for Hsp90 binding with a relative affinity of 15-20 microM. PU3 induces degradation of proteins, including Her2, in a manner similar to GM. Furthermore, PU3 inhibits the growth of breast cancer cells causing retinoblastoma protein hypophosphorylation, G1 arrest and differentiation. CONCLUSIONS: PU3 is representative of a novel class of synthetic compounds that binds to Hsp90 and inhibits the proliferation of cancer cells. These reagents could provide a new strategy for the treatment of cancers.
BACKGROUND: The Hsp90s contain a conserved pocket that binds ATP/ADP and plays an important role in the regulation of chaperone function. Occupancy of this pocket by several natural products (geldanamycin (GM) and radicicol) alters Hsp90 function and results in the degradation of a subset of proteins (i.e. steroid receptors, Her2, Raf). We have used the structural features of this pocket to design a small molecule inhibitor of Hsp90. RESULTS: The designed small molecule PU3 competes with GM for Hsp90 binding with a relative affinity of 15-20 microM. PU3 induces degradation of proteins, including Her2, in a manner similar to GM. Furthermore, PU3 inhibits the growth of breast cancer cells causing retinoblastoma protein hypophosphorylation, G1 arrest and differentiation. CONCLUSIONS:PU3 is representative of a novel class of synthetic compounds that binds to Hsp90 and inhibits the proliferation of cancer cells. These reagents could provide a new strategy for the treatment of cancers.
Authors: Pallav D Patel; Pengrong Yan; Paul M Seidler; Hardik J Patel; Weilin Sun; Chenghua Yang; Nanette S Que; Tony Taldone; Paola Finotti; Ralph A Stephani; Daniel T Gewirth; Gabriela Chiosis Journal: Nat Chem Biol Date: 2013-09-01 Impact factor: 15.040
Authors: Tony Taldone; Tai Wang; Anna Rodina; Naga Vara Kishore Pillarsetty; Chander S Digwal; Sahil Sharma; Pengrong Yan; Suhasini Joshi; Piyusha P Pagare; Alexander Bolaender; Gail J Roboz; Monica L Guzman; Gabriela Chiosis Journal: Cold Spring Harb Perspect Biol Date: 2020-04-01 Impact factor: 10.005
Authors: Tai Wang; Anna Rodina; Mark P Dunphy; Adriana Corben; Shanu Modi; Monica L Guzman; Daniel T Gewirth; Gabriela Chiosis Journal: J Biol Chem Date: 2018-11-08 Impact factor: 5.157