A potent and selective PAK1-inhibitor(s) from Astrazeneca!

ACS Med Chem Lett. 2016; 7(12): 1118-1123. 

Optimization of Highly Kinase Selective Bis-anilino Pyrimidine PAK1 Inhibitors.

McCoull W¹, Hennessy EJ², Blades K³, Chuaqui C², Dowling JE², Ferguson AD², Goldberg FW¹, Howe N³, Jones CR³, Kemmitt PD¹, Lamont G¹, Varnes JG², Ward RA¹, Yang B².

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.

MIA-602 (GHRH antagonist) is a new PAK1-blocking peptide!

Several years ago, a group led by Andrew Schally (1977 Nobel-laureate) at University of Miami developed a new peptide of 29 amino acids called MIA-602 which antagonizes with GHRH (growth-hormone releasing hormone) for its receptor, and found its potent anti-cancer activity (1). Very recently, a Chinese group in collaboration with Andrew Schally, nailed-down the precise molecular mechanism underlying its anti-cancer action. MIA-602 suppresses the PAK1 gene expression (2). Thus, MIA-602 is a new member of PAK1- blockers.

In other words, GHRH and its receptor are essential for activation of PAK1 gene, and if its receptor is abnormally activated somehow, a wide variety of PAK1-dependent diseases/disorders would emerge, and eventually shorten our lifespan. Interestingly, GH (growth-hormone)-deficient mice are dwarfs, but live longer than the wild-type (3). Thus, it is almost certain that MIA-602 extends our healthy lifespan. 

References: 
 1. Bellyei S¹, Schally AV, Zarandi M, Varga JL, Vidaurre I, Pozsgai E.

GHRH antagonists reduce the invasive and metastatic potential of human cancer cell lines in vitro. Cancer Lett. 2010 ; 293(1): 31-40.

2. Gan J¹, Ke X¹, Jiang J¹, Dong H¹, Yao Z¹, Lin Y¹, Lin W¹, Wu X², Yan S³, Zhuang Y², Chu WK⁴, Cai R^5,6,7,8,9, Zhang X^5,6,7,8,9, Cheung HS^5,6,10, Block NL¹¹, Pang CP^4,12, Schally AV^{13,6,7,8,9,11}, Zhang H^14,2,15. Growth hormone-releasing hormone receptor antagonists inhibit human gastric cancer through downregulation of PAK1-STAT3/NF-κB signaling. Proc Natl Acad Sci U S A. 2016 Dec 7.  

3. Kinney-Forshee BA¹, Kinney NE, Steger RW, Bartke A. Could a deficiency in growth hormone signaling be beneficial to the aging brain?  Physiol Behav. 2004; 80(5): 589-94.