FRAX597

FRAX597 is a small-molecule inhibitor of the group 1 p21-activated kinases (PAKs) with IC50 values of 8nM, 13nM and 19nM, respectively for PAK1, PAK2 and PAK3 [1].

The PAKs family includes two sub groups: 1 and 2. These kinases take participate in the growth of various types of cancers. FRAX597 is developed to be an inhibitor of group 1 PAKs from the initial hits of a high throughput screen. It is an ATP-competitive inhibitor of PAK 1-3. To group 2 PAKs, FRAX597 shows minimal inhibitory activity. The inhibition mechanism of FRAX597 is that it binds PAK by targeting the ATP binding site and competes with ATP. FRAX597 is reported to suppress cell proliferation by arresting cell cycle in G1 without impacting cell viability in Schwann cells. In vivo assay also demonstrates FRAX597 can suppress tumor growth in an orthotopic model of NF2. This effect on the cells has been proved to be mediated through the inhibition of the group I PAKs [1].

References:
[1] Silvia Licciulli, Jasna Maksimoska, Chun Zhou, Scott Troutman, Smitha Kota, Qin Liu, Sergio Duron, David Campbell, Jonathan Chernoff, Jeffery Field, Ronen Marmorstein and Joseph L. Kissil. FRAX597, a small molecule inhibitor of the p21-activated kinases, inhibits schwannomas tumorigenesis of NF2-associated. J. Biol. Chem. 2013, August.

FRAX597, a PAK1 inhibitor, synergistically reduces pancreatic cancer growth when combined with gemcitabine.[Pubmed:26774265]

BMC Cancer. 2016 Jan 16;16:24.

BACKGROUND: Pancreatic ductal adenocarcinoma remains one of the most lethal of all solid tumours. Treatment options are limited and gemcitabine-based chemotherapy remains the standard of care. Although growing evidence shows that p21-activated kinase 1 (PAK1) plays a crucial role in pancreatic cancer, its role has not been fully elucidated. This study aimed to characterise the expression and functional relevance of PAK1 in pancreatic cancer. METHODS: PAK1 expression was measured in pancreatic cancer specimens by immunohistochemistry and in pancreatic cancer cell lines by western blotting. The effect of inhibition of PAK1 by either shRNA knock-down (KD), or by a selective inhibitor, FRAX597, alone or in combination with gemcitabine, on cell proliferation and migration/invasion was measured by thymidine uptake and Boyden chamber assays, respectively. The effect on tumour growth and survival was assessed in orthotopic murine models. RESULTS: PAK1 was expressed in all human pancreatic cancer samples tested, an7d was upregulated in all pancreatic cancer cell lines tested. PAK1 KD inhibited pancreatic cancer cell growth and survival, and increased sensitivity to gemcitabine treatment. AKT activity and HIF1alpha expression were also inhibited. FRAX597 inhibited pancreatic cancer cell proliferation, survival, and migration/invasion. When combined with gemcitabine, FRAX597 synergistically inhibited pancreatic cancer proliferation in vitro and inhibited tumour growth in vivo. CONCLUSIONS: These results implicate PAK1 as a regulator of pancreatic cancer cell growth and survival. Combination of a PAK1 inhibitor such as FRAX597 with cytotoxic chemotherapy deserves further study as a novel therapeutic approach to pancreatic cancer treatment.

FRAX597, a small molecule inhibitor of the p21-activated kinases, inhibits tumorigenesis of neurofibromatosis type 2 (NF2)-associated Schwannomas.[Pubmed:23960073]

J Biol Chem. 2013 Oct 4;288(40):29105-14.

The p21-activated kinases (PAKs) are immediate downstream effectors of the Rac/Cdc42 small G-proteins and implicated in promoting tumorigenesis in various types of cancer including breast and lung carcinomas. Recent studies have established a requirement for the PAKs in the pathogenesis of Neurofibromatosis type 2 (NF2), a dominantly inherited cancer disorder caused by mutations at the NF2 gene locus. Merlin, the protein product of the NF2 gene, has been shown to negatively regulate signaling through the PAKs and the tumor suppressive functions of Merlin are mediated, at least in part, through inhibition of the PAKs. Knockdown of PAK1 and PAK2 expression, through RNAi-based approaches, impairs the proliferation of NF2-null schwannoma cells in culture and inhibits their ability to form tumors in vivo. These data implicate the PAKs as potential therapeutic targets. High-throughput screening of a library of small molecules combined with a structure-activity relationship approach resulted in the identification of FRAX597, a small-molecule pyridopyrimidinone, as a potent inhibitor of the group I PAKs. Crystallographic characterization of the FRAX597/PAK1 complex identifies a phenyl ring that traverses the gatekeeper residue and positions the thiazole in the back cavity of the ATP binding site, a site rarely targeted by kinase inhibitors. FRAX597 inhibits the proliferation of NF2-deficient schwannoma cells in culture and displayed potent anti-tumor activity in vivo, impairing schwannoma development in an orthotopic model of NF2. These studies identify a novel class of orally available ATP-competitive Group I PAK inhibitors with significant potential for the treatment of NF2 and other cancers.