Optimization of Pan-Pim Kinase Activity and Oral Bioavailability Leading to Diaminopyrazole (GDC-0339) for the Treatment of Multiple Myeloma

  • J Med Chem. 2019 Feb 28;62(4):2140-2153. doi: 10.1021/acs.jmedchem.8b01857.
Xiaojing Wang  1 ,  Wesley Blackaby  2 ,  Vivienne Allen  2 ,  Grace Ka Yan Chan  1 ,  Jae H Chang  1 ,  Po-Chang Chiang  1 ,  Coura Diène  2 ,  Jason Drummond  1 ,  Steven Do  1 ,  Eric Fan  1 ,  Eric B Harstad  1 ,  Alastair Hodges  2 ,  Huiyong Hu  1 ,  Wei Jia  1 ,  William Kofie  2 ,  Aleksandr Kolesnikov  1 ,  Joseph P Lyssikatos  1 ,  Justin Ly  1 ,  Mizio Matteucci  2 ,  John G Moffat  1 ,  Veerendra Munugalavadla  1 ,  Jeremy Murray  1 ,  David Nash  2 ,  Cameron L Noland  1 ,  Geoff Del Rosario  1 ,  Leanne Ross  1 ,  Craig Rouse  2 ,  Andrew Sharpe  2 ,  Dionysos Slaga  1 ,  Minghua Sun  1 ,  Vickie Tsui  1 ,  Heidi Wallweber  1 ,  Shang-Fan Yu  1 ,  Allen J Ebens  1
Affiliations
  • 1. Genentech, Inc. , 1 DNA Way , South San Francisco , California 94080 , United States.
  • 2. Charles River Discovery Research Services UK Limited (formerly BioFocus), Chesterford Research Park , Saffron Walden , Essex CB10 1XL , United Kingdom.
Abstract

Pim Kinases have been targets of interest for a number of therapeutic areas. Evidence of durable single-agent efficacy in human clinical trials validated Pim kinase inhibition as a promising therapeutic approach for Multiple Myeloma patients. Here, we report the compound optimization leading to GDC-0339 (16), a potent, orally bioavailable, and well tolerated pan-Pim kinase inhibitor that proved efficacious in RPMI8226 and MM.1S human Multiple Myeloma xenograft mouse models and has been evaluated as an early development candidate.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • 99.87%, Pim Inhibitor
    target: Pim
    Research Areas: Cancer