Selectivity switch between FAK and Pyk2: Macrocyclization of FAK inhibitors improves Pyk2 potency

  • Bioorg Med Chem Lett. 2016 Dec 15;26(24):5926-5930. doi: 10.1016/j.bmcl.2016.10.092.
Julie Farand  1 ,  Nicholas Mai  2 ,  Jayaraman Chandrasekhar  3 ,  Zachary E Newby  4 ,  Josh Van Veldhuizen  5 ,  Jennifer Loyer-Drew  5 ,  Chandrasekar Venkataramani  2 ,  Juan Guerrero  2 ,  Amy Kwok  6 ,  Ning Li  6 ,  Yelena Zherebina  6 ,  Sibylle Wilbert  7 ,  Jeff Zablocki  2 ,  Gary Phillips  5 ,  William J Watkins  2 ,  Robert Mourey  8 ,  Gregory T Notte  2
Affiliations
  • 1. Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA. Electronic address: [email protected].
  • 2. Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
  • 3. Department of Structural Chemistry, Gilead Sciences, Inc., 199 East Blaine Street, Seattle, WA 98102, USA.
  • 4. Department of Structural Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
  • 5. Department of Medicinal Chemistry, Gilead Sciences, Inc., 199 East Blaine Street, Seattle, WA 98102, USA.
  • 6. Department of Biology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
  • 7. Department of Drug Metabolism, Gilead Sciences, Inc., 199 East Blaine Street, Seattle, WA 98102, USA.
  • 8. Department of Biology, Gilead Sciences, Inc., 199 East Blaine Street, Seattle, WA 98102, USA.
PMID: 27876318 DOI: 10.1016/j.bmcl.2016.10.092
Abstract

Herein, we describe the synthesis of Pyk2 inhibitors via macrocyclization of FAK and dual Pyk2-FAK inhibitors. We identified macrocycle 25a as a highly potent Pyk2 Inhibitor (IC50=0.7nM), with ∼175-fold improvement in Pyk2 potency as compared to its acyclic counterpart. In many cases, macrocyclization improved Pyk2 potency while weakening FAK potency, thereby improving the Pyk2/FAK selectivity ratio for this structural class of inhibitors. Various macrocyclic linkers were studied in an attempt to optimize Pyk2 selectivity. We observed macrocyclic atropisomerism during the synthesis of 19-membered macrocycles 10a-d, and successfully obtained crystallographic evidence of one atropisomer (10a-AtropB) preferentially bound to Pyk2.

Keywords
Atropisomer; FAK; Glioblastoma; Macrocycle; Pyk2.