2. Academic Validation
  3. Selectivity switch between FAK and Pyk2: Macrocyclization of FAK inhibitors improves Pyk2 potency

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

Affiliations

  • 1 Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA. Electronic address: Julie.Farand@gilead.com.
  • 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.

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