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.

“Wonder Drug” (15K) for cancer therapy and improving our QOL

Preface

In our long human history, there appeared a series of wonder drugs that have saved millions’ lives. One of the oldest wonder drugs is called propolis, a bee-made antibiotics, that has been used as a traditional medicine over 4000 years since the ancient Egyptian era. Not only healing wounds and inflammatory diseases, it was used to keep the body of deceased royal family intact under Pyramid for almost forever by preparing mummies. Another old wonder drug is called “Aspirin”, a pain-killer developed by a Bayer chemist, from the herbal medicine “salicylic acid”.  The first man-made wonder drug used to be called “606” or “Salvarsan”. It is an aniline dye coupled with arsenate, developed by the 1908 Nobel-laureate Paul Ehrlich in 1909. It kills the syphilis-causing bacteria “Spirohaeta”. Since then Dr. Ehrlich has been remembered as the “father of chemotherapy”. In 1940, MGM made a film entitled “Dr. Ehrlich’s Magic Bullet”.

An old man called “Charlie” in this drama based on the true story entitled “Charlie’s Angels” was inspired by this old film during his student days, and decided to be a scientist, instead of being an artistic painter, to make his own magic bullet killing the formidable cancers. Shortly after the end of WW II, Charlie and his younger sisters were once contracted with a deadly disease called “TB” (tuberculosis), but saved by another wonder drug called PAS (p-aminosalicylate) developed by a Swedish chemist. Charlie’s strong determination for developing his own magic bullet was solidified by these two historic events during his youth.

The wonder drug developed by this international team “Charlie’s Angels” in 21th century is called HT-192 or 15K.  It was synthesized by a young Ph. D. student called “Hideaki” in Japan from an old acidic pain-killer called “Ketorolac”. It was his 192th chemical compounds that he synthesized towards the end of  his 2 years graduate student life under the supervision of Charlie, an old man living in Australia. “K” stands for Ketorolac and "15" is its birth year (2015). 15K is a highly cell-permeable ester of Ketorolac synthesized by a simple cupper-catalyzed reaction called “Click Chemistry” which was originally developed by the 2001 Nobel-laureate (Barry Sharpless). 

This team includes another brilliant young  Ph.D. student called “Binh” from Vietnam. Binh found that the anti-cancer activity of Ketorolac was boosted over 500-fold by this Click Chemistry. Ketorolac is a PAK1-blocker, and its anti-PAK1 activity was also boosted over 500-fold by this esterization. It marked a new "Guinness record" in PAK research!  PAK1 is the major oncogenic/ ageing kinase that Charlie has worked on for 4 decades since his NIH days. This enzyme is required for the growth of cancers (in particular solid tumors) and definitely shortens our lifespan. In other words, PAK1-blockers in general are cancer-killers and elixirs, but causing no side effect. That is the reason why they called 15K a wonder drug, and filed a patent. Interestingly, propolis is also among herbal PAK1-blockers which indeed extend our healthy lifespan. In fact they managed to boost the anti-cancer activity of a propolis ingredient called caffeic acid (CA) over 400-fold by the Click Chemistry as well.

They expected that 15K is worth 200 million dollars, if they can manage to sell the license to pharmaceutical giants such as Roche, Novartis and Pfeizer who are fiercely fighting/racing to develop the very first FDA-approved PAK1-blocker. Interestingly, Ketorolac was developed as a pain-killer by Roche more than 3 decades ago, and recently the 1987 Nobel-laureate (Susumu Tonegawa) managed to sell the license (worth 200 million dollars) on his own PAK1-blocker series (FRA 1234) to Roche. Unfortunately, however, FRA1234 turned out to be both water-insoluble and poorly cell-permeable. 

Thus, Charlie recently decided to develop both water-soluble and highly cell-permeable PAK1- blockers from Ketorolac, and his team eventually succeeded in realizing their own dream by the Click Chemistry. There is no doubt that 15K would pave a smooth path for Barry Sharpless to receive his second Nobel prize, when 15K is successfully marketed as a wonder drug in a decade or so, finally establishing that 1,2,3-triazolyl ester is a powerful cell-permeable vector for the delivery of COOH-bearing drugs. 

Blocking the oncogenic kinase PAK1 induces "autophagy" in cancer cells and extends the healthy lifespan.

"Ivermection" ,  that was developed by Prof. Satoshi Omura (2015 Nobel laureate) at Kitasato Institute in Tokyo in 1980s, blocks the oncogenic/ageing kinase PAK1 in cancer cells and inhibits their growth (1). Based on this observation of ours, a Chinese group recently found that the PAK1-blocker "Ivermectin" induces the cytostatic "autophagy" in cancer cells, by further down-regulating another oncogenic kinase AKT (2).  Interestingly, this year Prof. Yoshinori Ohsumi at Tokyo Institute of Technology is expected to receive the 2016 Nobel prize in Physiology/Medicine for his pioneer work on "autophagy" based on genetic analysis of yeast mutants. Thus, two Nobel-winning discoveries linked each other through a third discovery (PAK family kinases such as PAK1) by us in 1977 (in amoebae) at NIH and 1994 (in mammals) at Singapore National University.

Phosphorylation of ATG13 blocks the autophagy

Interestingly, rapamycin which is an inhibitor of another oncogenic/ageing kinase TOR, also induces the autophagy in cancer cells, and TOR directly phosphorylates the ATG13, eventually inactivating the autophagic kinase ATG1 (3).  Moreover, expression of a “non-phosphorylatable” mutant of ATG13 in cells alone induces the autophagy without starvation or rapamycin treatment (3). 

Thus, our obvious immediate question is whether PAK1 also phosphorylates ATG13 directly,  or through activating the oncogenic AKT-TOR signaling pathway.


The autophahy contributes to the longevity
Rapamycin as well as a series of herbal PAK1-blockers such as propolis extend the healthy lifespan of small animals such as C. elegans and mice. Thus, starvation, less-eating (calorie-restriction) or exercise, which also induce the autophagy, also promote the longevity by down-reglating the (oncogenic or anti-autophagic/ageing) PAK1-AKT-TOR signaling pathway.


References: 

1. Hashimoto H¹, Messerli SM, Sudo T, Maruta H.
Ivermectin inactivates the kinase PAK1 and blocks the PAK1-dependent growth of human ovarian cancer and NF2 tumor cell lines. Drug Discov Ther. 2009 ; 3(6): 243-6.

2. Dou Q¹, Chen HN², Wang K³, Yuan K¹, Lei Y⁴, Li K¹, Lan J³, Chen Y¹, Huang Z¹, Xie N¹, Zhang L¹, Xiang R⁵, Nice EC⁶, Wei Y¹, Huang C⁷
Ivermectin Induces Cytostatic Autophagy by Blocking the PAK1/Akt Axis in Breast Cancer. Cancer Res. 2016 ; 76(15): 4457-69. 

3. Kamada Y¹, Yoshino K, Kondo C, Kawamata T, Oshiro N, Yonezawa K, Ohsumi Y.

Tor directly controls the Atg1 kinase complex to regulate autophagy. Mol Cell Biol. 2010 ; 30(4): 1049-58.