P21-activated kinase 5 (PAK5) belongs to the PAK-II subfamily, which is an important regulator of cell survival, adhesion, and motility. However, the functions of PAK5 in endometriosis remain unclear. Here, PAK5 is strikingly upregulated in endometriosis. Furthermore, the knockdown of PAK5 or its inhibitor GNE 2861 blocks the development of endometriosis, which is equally demonstrated in PAK5-knockout mice. In addition, PAK5 promotes glycolysis by enhancing the protein stability of pyruvate kinase 2 (PKM2) in endometriotic cells, which is a key enzyme for glucose metabolism. Moreover, the phosphorylation of PKM2 at Ser519 by PAK5 mediates endometriosis cell proliferation and metastasis. Collectively, PAK5 plays an indispensable role in endometriosis. Our findings demonstrate that PAK5 is an important target for the treatment of endometriosis.

01 Dec 2024·European Journal of Medicinal Chemistry

Design, synthesis and biological evaluation of novel benzimidazole-derived p21-activited kinase 4 (PAK4) inhibitors bearing a 4-(4-methylpiperazin-1-yl)phenyl scaffold as potential antitumor agents

Article

Author: Cai, Zheng-hao ; Hao, Shuang ; Niu, Yi-Fan ; Niu, Yi-fan ; Meng, Fan-Hao ; Wang, Jia-hui ; Yan, Jing-Han ; Meng, Fan-hao ; Li, Feng ; Yan, Jing-han ; Hou, Liang ; Cai, Zheng-Hao ; Wang, Jia-Hui

A series of novel 6-(4-(4-methylpiperazin-1-yl)phenyl)-1H-benzo[d]imidazole-based p21-activited kinase 4 (PAK4) inhibitors were designed and synthesized based on the structure of lead compound GNE-2861 and that of anticancer inhibitors reported in our previous studies. All target compounds so designed were preliminarily screened in vitro for anti-tumor potency through kinase inhibitory assays and MTT assays, which revealed that most compounds exhibited significant inhibitory effects on PAK4 enzyme as well as prominent antiproliferative activities against four cancer cell models (A549, NCI-H1975, MDA-MB-231 and SK-BR-3) and low damage to healthy cells. In particular, the hit compound 12i was identified as the most effective and rather selective compound both at the enzyme and cellular level. Meanwhile, molecular docking and dynamic studies disclosed that compound 12i could bind to PAK4 stably via multiple interactions applied between the compound and the enzyme. Further mechanism studies indicated that compound 12i could inhibit the proliferation and suppress the migratory potential of MDA-MB-231 cells by inhibiting the phosphorylation of PAK4 and LIMK1, arresting cell cycle in the G0/G1 phase, inducing apoptosis and promoting ROS production. Notably, compound 12i could effectively inhibit triple-negative breast cancer (TNBC) growth with little toxicity in the MDA-MB-231 cell xenograft model. Taken together, in vitro and in vivo results demonstrated that compound 12i possessed high drug potential as an inhibitor of PAK4 to inhibit the growth and metastasis of TNBC.

01 Oct 2023·British journal of cancer

Combined blockade of mTOR and p21-activated kinases pathways prevents tumour growth in KRAS-mutated colorectal cancer.

Article

Author: Formisano, Luigi ; Franco, Renato ; Ascione, Claudia Maria ; Pesapane, Ada ; Marino, Federica Zito ; Esposito, Daniela ; Troiani, Teresa ; Napolitano, Fabiana ; Belli, Stefania ; Zambrano, Nicola ; Allotta, Alessandra ; Bianco, Roberto ; Servetto, Alberto

BACKGROUNDThe identification of novel therapeutic strategies for metastatic colorectal cancer (mCRC) patients harbouring KRAS mutations represents an unmet clinical need. In this study, we aimed to clarify the role of p21-activated kinases (Paks) as therapeutic target for KRAS-mutated CRC.METHODSPaks expression and activation levels were evaluated in a cohort of KRAS-WT or -mutated CRC patients by immunohistochemistry. The effects of Paks inhibition on tumour cell proliferation and signal transduction were assayed by RNAi and by the use of three pan-Paks inhibitors (PF-3758309, FRAX1036, GNE-2861), evaluating CRC cells, spheroids and tumour xenografts' growth.RESULTSPaks activation positively correlated with KRAS mutational status in both patients and cell lines. Moreover, genetic modulation or pharmacological inhibition of Paks led to a robust impairment of KRAS-mut CRC cell proliferation. However, Paks prolonged blockade induced a rapid tumour adaptation through the hyper-activation of the mTOR/p70S6K pathway. The addition of everolimus (mTOR inhibitor) prevented the growth of KRAS-mut CRC tumours in vitro and in vivo, reverting the adaptive tumour resistance to Paks targeting.CONCLUSIONSIn conclusion, our results suggest the simultaneous blockade of mTOR and Pak pathways as a promising alternative therapeutic strategy for patients affected by KRAS-mut colorectal cancer.

100 Deals associated with GNE-2861

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Indication	Highest Phase	Country/Location	Organization	Date
Endometriosis	Preclinical	China	Peking University Third Hospital	27 Sep 2024
Endometriosis	Preclinical	China	The Second Hospital of Shandong University	27 Sep 2024
Neoplasms	Discovery	United States	Genentech, Inc.	04 Feb 2014

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