Optimization of Highly Kinase Selective Bis-anilino Pyrimidine PAK1 Inhibitors

  • ACS Med Chem Lett. 2016 Sep 14;7(12):1118-1123. doi: 10.1021/acsmedchemlett.6b00322.
William McCoull  1 ,  Edward J Hennessy  2 ,  Kevin Blades  3 ,  Claudio Chuaqui  2 ,  James E Dowling  2 ,  Andrew D Ferguson  2 ,  Frederick W Goldberg  1 ,  Nicholas Howe  3 ,  Christopher R Jones  3 ,  Paul D Kemmitt  1 ,  Gillian Lamont  1 ,  Jeffrey G Varnes  2 ,  Richard A Ward  1 ,  Bin Yang  2
Affiliations
  • 1. AstraZeneca , 310 Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, U.K.
  • 2. AstraZeneca , Gatehouse Park, Waltham, Massachusetts 02451, United States.
  • 3. AstraZeneca , Alderley Park, Macclesfield, Cheshire, SK10 4TG, U.K.
PMID: 27994749 DOI: 10.1021/acsmedchemlett.6b00322
Abstract

Group I p21-activated kinase (PAK) inhibitors are indicated as important in Cancer progression, but achieving high kinase selectivity has been challenging. A bis-anilino pyrimidine PAK1 Inhibitor was identified and optimized through structure-based drug design to improve PAK1 potency and achieve high kinase selectivity, giving in vitro probe compound AZ13705339 (18). Reduction of lipophilicity to lower clearance afforded AZ13711265 (14) as an in vivo probe compound with oral exposure in mouse. Such probes will allow further investigation of PAK1 biology.

Keywords
LLE; PAK; bis-anilino pyrimidine; kinase selectivity; probe.
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