2. Academic Validation
  3. Discovery of (2S)-1-[4-(2-{6-amino-8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9H-purin-9-yl}ethyl)piperidin-1-yl]-2-hydroxypropan-1-one (MPC-3100), a purine-based Hsp90 inhibitor

Discovery of (2S)-1-[4-(2-{6-amino-8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9H-purin-9-yl}ethyl)piperidin-1-yl]-2-hydroxypropan-1-one (MPC-3100), a purine-based Hsp90 inhibitor

  • J Med Chem. 2012 Sep 13;55(17):7480-501. doi: 10.1021/jm3004619.
Se-Ho Kim 1,  Ashok Bajji,  Rajendra Tangallapally,  Benjamin Markovitz,  Richard Trovato,  Mark Shenderovich,  Vijay Baichwal,  Paul Bartel,  Daniel Cimbora,  Rena McKinnon,  Rosann Robinson,  Damon Papac,  Daniel Wettstein,  Robert Carlson,  Kraig M Yager
Affiliations

Affiliation

  • 1 Myrexis Inc., 305 Chipeta Way, Salt Lake City, Utah 84108, USA. seho.kimkim@gmail.com
PMID: 22913511 DOI: 10.1021/jm3004619
Abstract

Modulation of HSP90 (heat shock protein 90) function has been recognized as an attractive approach for Cancer treatment, since many Cancer cells depend on HSP90 to maintain cellular homeostasis. This has spurred the search for small-molecule HSP90 inhibitors. Here we describe our lead optimization studies centered on the purine-based HSP90 Inhibitor 28a containing a piperidine moiety at the purine N9 position. In this study, key SAR was established for the piperidine N-substituent and for the congeners of the 1,3-benzodioxole at C8. These efforts led to the identification of orally bioavailable 28g that exhibits good in vitro profiles and a characteristic molecular biomarker signature of HSP90 inhibition both in vitro and in vivo. Favorable pharmacokinetic properties along with significant antitumor effects in multiple human Cancer xenograft models led to the selection of 28g (MPC-3100) as a clinical candidate.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-13301
    98.3%, HSP抑制剂
    HSP
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