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