Discovery and the structural basis of a novel p21-activated kinase 4 inhibitor

Ryu, Beyong Hwan; Kim, Sunmin; Min, Bora; Kim, Keon Young; Lee, Jin Soo; Park, Whui Jung; Lee, Hyuk; Kim, Seong Hwan; Park, SangYoun

doi:10.1016/j.canlet.2014.03.024

Cited by 35 publications

(18 citation statements)

References 22 publications

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“…Being a natural agent, it most likely has pleiotropic effects complicating its development as a therapeutic agent. A recent group, using high throughput screening and structure based drug design, identified a novel PAK4 inhibitor, KY-04031 (36). Unfortunately, KY-04031 showed very low binding affinity towards PAK4 and required high micro molar concentrations to inhibit cell proliferation in PAK4 dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Novel p21-Activated Kinase 4 (PAK4) Allosteric Modulators Overcome Drug Resistance and Stemness in Pancreatic Ductal Adenocarcinoma

Aboukameel

Muqbil

Senapedis

et al. 2017

Molecular Cancer Therapeutics

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The p21-activated kinase 4 (PAK4) is a key downstream effector of the Rho family GTPases and is found to be over-expressed in pancreatic ductal adenocarcinoma (PDAC) cells but not in normal human pancreatic ductal epithelia (HPDE). Gene copy number amplification studies in PDAC patient cohorts confirmed PAK4 amplification making it an attractive therapeutic target in PDAC. We investigated the anti-tumor activity of novel PAK4 allosteric modulators (PAMs) on a panel of PDAC cell lines and chemotherapy resistant flow sorted PDAC cancer stem cells (CSCs). The toxicity and efficacy of PAMs were evaluated in multiple sub-cutaneous mouse models of PDAC. PAMs (KPT-7523, KPT-7189, KPT-8752, KPT-9307 and KPT-9274) show anti-proliferative activity in vitro against different PDAC cell lines while sparing normal HPDE. Cell growth inhibition was concurrent with apoptosis induction and suppression of colony formation in PDAC. PAMs inhibited proliferation and anti-apoptotic signals downstream of PAK4. Coimmunoprecipitation experiments showed disruption of PAK4 complexes containing vimentin. PAMs disrupted CSC spheroid formation through suppression of PAK4. Moreover PAMs synergize with gemcitabine and oxaliplatin in vitro. KPT-9274, currently in a Phase I clinical trial (clinicaltrials.gov; NCT02702492), possesses desirable PK properties and is well tolerated in mice with the absence of any signs of toxicity when 200 mg/kg daily is administered either intravenously or orally. KPT-9274 as a single agent showed remarkable anti-tumor activity in subcutaneous xenograft models of PDAC cell lines and CSCs. These proof-of-concept studies demonstrated the anti-proliferative effects of novel PAK4 allosteric modulators in PDAC and warrant further clinical investigations.

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Section: Discussionmentioning

confidence: 99%

Novel p21-Activated Kinase 4 (PAK4) Allosteric Modulators Overcome Drug Resistance and Stemness in Pancreatic Ductal Adenocarcinoma

Aboukameel

Muqbil

Senapedis

et al. 2017

Molecular Cancer Therapeutics

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“…Therefore, we are trying to develop novel oral available PAK4 inhibitors with antiresorptive activity and/or anticancer activity. (50) The upstream molecules to activate PAK4 during osteoclast differentiation might be identified in a further study. Basically, small GTPases including RhoA, Rac, and Cdc42 have been shown to regulate osteoclast function and bone resorption as upstream signaling molecules of PAK.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the ovariectomized model was not carried out in this study because PF‐3758309 with the undesirable pharmacokinetic characteristics and the lack of an observed dose‐response relationship in the phase I might not be enough for its oral administration. Therefore, we are trying to develop novel oral available PAK4 inhibitors with antiresorptive activity and/or anticancer activity …”

Section: Discussionmentioning

confidence: 99%

Repositioning Potential of PAK4 to Osteoclastic Bone Resorption

Choi

Yeon

Ryu

et al. 2015

Journal of Bone and Mineral Research

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Drug repositioning is a rational approach for expanding the use of existing drugs or candidate drugs to treat additional disorders. Here we investigated the possibility of using the anticancer p21-activated kinase 4 (PAK4)-targeted inhibitor PF-3758309 to treat osteoclast-mediated disorders. PAK4 was highly expressed in bone marrow cells and was phosphorylated during their differentiation into osteoclasts, and osteoclast differentiation was significantly inhibited by the dominant negative form of PAK4 and by PF-3758309. Specifically, PF-3758309 significantly inhibited the fusion of preosteoclasts, the podosome formation, and the migration of preosteoclasts. PF-3758309 also had in vivo antiresorptive activity in a lipopolysaccharide-induced bone erosion model and in vitro antiosteoclastogenic activity in the differentiation of human bone marrow-derived cells and peripheral blood mononuclear cells into osteoclasts. These data demonstrate the relevance of PAK4 in osteoclast differentiation and the potential of PAK4 inhibitors for treating osteoclast-related disorders.

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“…-[1H-indazol-5-yl]-6-methoxy-1,3,5triazine-2,4-diamine), was discovered [16]. Being yet another ATP-competitive inhibitor, KY-04031 showed very low binding affinity against PAK4 and also required high micromolar concentrations in order to inhibit cell proliferation in a PAK4-dependent manner.…”

Section: Pak4 Inhibitor Ky-04031 (N[2]-[2-{1h-indol-3-yl} Ethyl]-n[4]mentioning

confidence: 98%

P21-Activated Kinase 4: A Druggable Target in the Elusive Oncogenic Kras Pathway?

Azmi

Mohammad

2015

Future Med. Chem.

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Discovery and the structural basis of a novel p21-activated kinase 4 inhibitor

Cited by 35 publications

References 22 publications

Novel p21-Activated Kinase 4 (PAK4) Allosteric Modulators Overcome Drug Resistance and Stemness in Pancreatic Ductal Adenocarcinoma

Novel p21-Activated Kinase 4 (PAK4) Allosteric Modulators Overcome Drug Resistance and Stemness in Pancreatic Ductal Adenocarcinoma

Repositioning Potential of PAK4 to Osteoclastic Bone Resorption

P21-Activated Kinase 4: A Druggable Target in the Elusive Oncogenic Kras Pathway?

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