A novel orally bioavailable compound KPT-9274 inhibits PAK4, and blocks triple negative breast cancer tumor growth

Rane, Chetan K.; Senapedis, William; Baloglu, Erkan; Landesman, Yosef; Crochiere, Marsha; Das-Gupta, Soumyasri; Minden, Audrey

doi:10.1038/srep42555

Cited by 58 publications

(50 citation statements)

References 60 publications

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“…Thus, confirmation of an anti-cystic effect in several separate models of ADPKD, in vitro, ex vivo , and in vivo , strengthens our conclusions regarding the potential utility of this inhibitor for treatment of the human disease. Research from our laboratory showed that when KPT-9274 was orally administered to a 786-O (VHL-mut) human RCC xenograft model, there was dose-dependent inhibition of tumor growth with minimal toxicity 9 , data which is in line with several other recent publications from other institutions when KPT-9274 was administered both intravenously 18 and orally 16,17 , the latter up to 42 days 17 . Currently, KPT-9274 is being evaluated in a Phase 1 human clinical trial in patients with advanced solid malignancies or NHL (NCT02702492), thus there have been toxicity studies performed in a variety of animal models that allowed initiation of this clinical study.…”

Section: Discussionsupporting

confidence: 88%

“…It can be seen that total-PAK4 and to a lesser extent total-β-catenin, were decreased in the kidneys from treated animals (Fig. 5b), consistent with target engagement of KPT-9274 17 . In the Pkd1 flox/flox :Pkhd1-Cre mice, KPT-9274 treatment resulted in significantly decreased cyst growth, kidney size, and BUN when compared to vehicle treated controls (Fig.…”

Section: Resultssupporting

confidence: 64%

“…1a) that shows dual inhibition of PAK4 and NAMPT 9,15,17,18 . When injected into rats, the compound and its acetylated metabolite were found by LC-MS analysis to be present in plasma and bile but undetectable in urine (unpublished observations).…”

Section: Resultsmentioning

confidence: 99%

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Anticystogenic activity of a small molecule PAK4 inhibitor may be a novel treatment for autosomal dominant polycystic kidney disease

Hwang

Zhou

Chen

et al. 2017

Kidney International

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Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a common hereditary renal disease with no current available targeted therapies. Based on the established connection between β-catenin signaling and renal ciliopathies, and on data from our and other laboratories showing striking similarities of this disease and cancer, we evaluated the use of an orally bioavailable small molecule, KPT-9274 (a dual inhibitor of the protein kinase PAK4 and nicotinamide phosphoribosyl transferase), for treatment of ADPKD. Treatment of PKD-derived cells with this compound not only reduces PAK4 steady state protein levels and regulates β-catenin signaling, but also inhibits nicotinamide phosphoribosyl transferase, the rate-limiting enzyme in a key NAD salvage pathway. KPT-9274 can attenuate cellular proliferation and induce apoptosis associated with a decrease in active (phosphorylated) PAK4 and β-catenin in several PKD1-null murine cell lines, with a less pronounced effect on the corresponding phenotypically normal cells. Additionally, KPT-9274 shows inhibition of cytogenesis in an ex vivo model of cyclic AMP-induced cystogenesis as well as in the early stage Pkd1flox/flox:Pkhd1-Cre mouse model, the latter showing confirmation of specific anti-proliferative, apoptotic and on-target effects. NAD biosynthetic attenuation by KPT-9274, while critical for highly proliferative cancer cells, does not appear to be important in the slower growing cystic epithelial cells during cystogenesis. KPT-9274 was not toxic in our ADPKD animal model or in other cancer models. Thus, this small molecule inhibitor could be evaluated in a clinical trial as a viable therapy of ADPKD.

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Section: Discussionsupporting

confidence: 88%

Section: Resultssupporting

confidence: 64%

See 1 more Smart Citation

Anticystogenic activity of a small molecule PAK4 inhibitor may be a novel treatment for autosomal dominant polycystic kidney disease

Hwang

Zhou

Chen

et al. 2017

Kidney International

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“…Given our biochemical findings, the structural features of KPT-9274, and reports suggesting NAMPT as a target of KPT-9274 in other systems, [41][42][43][44] we tested whether KPT-9274 acts through a pathway involving NAMPT inhibition in AML cells. Protein expression of NAMPT was variable in a panel of malignant myeloid cell lines and primary AML cells, as shown in Figure 3A.…”

Section: Nampt As the Primary Target Of Kpt-9274 In Aml-treated Cellsmentioning

confidence: 99%

Selective targeting of NAMPT by KPT-9274 in acute myeloid leukemia

Mitchell¹,

Larkin²,

Grieselhuber³

et al. 2019

Blood Advances

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Key Points• KPT-9274, via its protein target NAMPT, diminishes NAD 1 levels and cellular respiration, leading to cell death.• Orally bioavailable KPT-9274 exhibits targetspecific activity in cell lines and patientderived xenograft models of AML. Treatment options for acute myeloid leukemia (AML) remain extremely limited and associated with significant toxicity. Nicotinamide phosphoribosyltransferase (NAMPT) is involved in the generation of NAD 1 and a potential therapeutic target in AML. We evaluated the effect of KPT-9274, a p21-activated kinase 4/NAMPT inhibitor that possesses a unique NAMPT-binding profile based on in silico modeling compared with earlier compounds pursued against this target. KPT-9274 elicited loss of mitochondrial respiration and glycolysis and induced apoptosis in AML subtypes independent of mutations and genomic abnormalities. These actions occurred mainly through the depletion of NAD 1 , whereas genetic knockdown of p21-activated kinase 4 did not induce cytotoxicity in AML cell lines or influence the cytotoxic effect of KPT-9274. KPT-9274 exposure reduced colony formation, increased blast differentiation, and diminished the frequency of leukemia-initiating cells from primary AML samples; KPT-9274 was minimally cytotoxic toward normal hematopoietic or immune cells. In addition, KPT-9274 improved overall survival in vivo in 2 different mouse models of AML and reduced tumor development in a patient-derived xenograft model of AML.Overall, KPT-9274 exhibited broad preclinical activity across a variety of AML subtypes and warrants further investigation as a potential therapeutic agent for AML.

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“…PAK4 is involved in a variety of cytoskeletal regulation such as promoting filopodia formation, dissolution of stress fibers, controlling actin polymerization and depolymerization as well as focal adhesion turnover [19][20][21][22][23][24][25] . Consistently, PAK4 overexpression is correlated with poor patient outcome in breast cancer patients, and its overexpression in breast cancer cell lines was shown to increase cell survival, anchorage-independent growth, cell migration and invasion [26][27][28][29][30] . PAK4 also plays an essential role during embryonic development, as complete depletion of PAK4 in mice caused embryonic lethality with severe defects in the heart, brain, and vasculature of the animals; however, its role in mammary gland development has not been investigated [31][32][33] .…”

Section: Introductionmentioning

confidence: 76%

Normal mammary gland development after MMTV-Cre mediated conditional PAK4 gene depletion

Rabieifar

Zhuang

Costa

et al. 2019

Preprint

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p21-activated protein kinases (PAKs) are serine/threonine kinases functioning as downstream effectors of the small GTPases Rac1 and Cdc42. Members of the PAK family are overexpressed in human breast cancer, but their role in mammary gland development is not fully explored. Here we examined the functional role of PAK4 in mammary gland development by creating a mouse model of MMTV-Cre driven conditional PAK4 gene depletion in the mammary gland. The PAK4 conditional knock-out mice were born healthy with no observed developmental deficits. Mammary gland whole-mounts revealed no defects in ductal formation or elongation of the mammary tree through the fat pad. PAK4 gene depletion also did not alter proliferation and invasion of the mammary epithelium in young virgin mice. Moreover, adult mice gave birth to healthy pups with normal body weight upon weaning. This implies that MMTV-Cre induced gene depletion of PAK4 in mice does not impair normal mammary gland development and thereby provides an in vivo model for examination of the potential function of PAK4 in breast cancer.

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A novel orally bioavailable compound KPT-9274 inhibits PAK4, and blocks triple negative breast cancer tumor growth

Cited by 58 publications

References 60 publications

Anticystogenic activity of a small molecule PAK4 inhibitor may be a novel treatment for autosomal dominant polycystic kidney disease

Anticystogenic activity of a small molecule PAK4 inhibitor may be a novel treatment for autosomal dominant polycystic kidney disease

Selective targeting of NAMPT by KPT-9274 in acute myeloid leukemia

Normal mammary gland development after MMTV-Cre mediated conditional PAK4 gene depletion

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