A FAK/PYK2 dual inhibitor
PF-431396 is dual focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (PYK2) inhibitor (IC50 values are 2 and 11 nM respectively), PF-431396 has a Kd value of 445 nM for BRD4.IC50 value: 2 nM (FAK); 11 nM (PYK2); 445 nM (KD for BRD4) [1] [2]Target: FAK; PYK2; BRD4in vitro: PF-431396 is a potent and highly selective pyrimidine-based inhibitor of both Pyk2 and FAK, Consistent with the idea that the tyrosine phosphorylation of Pyk2 and FAK involves an initial autophosphorylation or transphosphorylation step, treating A20 cells with PF-431396 blocked anti-Ig-induced tyrosine phosphorylation of Pyk2 and FAK when the cells were stimulated in suspension when they were stimulated on ECM [3]. Nanomolar affinities were also determined for PF-431396 (Kd = 445 ± 42 nM) and for the PIM inhibitor (Kd = 565 ± 63 nM) [2].
参考文献:
[1]. Buckbinder L, et al. Proline-rich tyrosine kinase 2 regulates osteoprogenitor cells and bone formation, and offers an anabolic treatment approach for osteoporosis. Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10619-24.
[2]. Ciceri P, et al. Dual kinase-bromodomain inhibitors for rationally designed polypharmacology. Nat Chem Biol. 2014 Mar 2.
[3]. Tse KW, et al. B cell receptor-induced phosphorylation of Pyk2 and focal adhesion kinase involves integrins and the Rap GTPases and is required for B cell spreading. J Biol Chem. 2009 Aug 21;284(34):22865-77.
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