Synonyms: KPT-9274 | KPT9274 | PAK4-IN-1
Compound class:
Synthetic organic
Comment: KPT-9274 is a small molecule that has reported inhibitory activity against PAK4 and NAMPT [3,6]. It is being developed by Karyopharm Therapeutics for anti-cancer efficacy in solid tumours [2,5] and in B cell malignancies [7]. KPT-9274 is suggested to act as an allosteric modulator of PAK4 that does not interfere with the enzyme's kinase activity (in contrast to the type 1 ATP-competitive PAK kinase inhibitor PF-3758309). It produces dose-dependent antitumour effects in solid and haematologic cell lines at low nanomolar concentrations [1]. KPT-9274 is claimed as example 728 in patent WO2015003166A1 [4].
The chemical structure of KPT-9274 is identical to that which was submitted to the WHO for the INN padnarsertib (proposed INN list 126, Jan 2022). |
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References |
1. Aboukameel A, Muqbil I, Senapedis W, Baloglu E, Landesman Y, Shacham S, Kauffman M, Philip PA, Mohammad RM, Azmi AS. (2017)
Novel p21-Activated Kinase 4 (PAK4) Allosteric Modulators Overcome Drug Resistance and Stemness in Pancreatic Ductal Adenocarcinoma. Mol Cancer Ther, 16 (1): 76-87. [PMID:28062705] |
2. Abril-Rodriguez G, Torrejon DY, Liu W, Zaretsky JM, Nowicki TS, Tsoi J, Puig-Saua C, Baselga-Carretero I, Medina E, Quist MJ et al.. (2019)
PAK4 inhibition improves PD-1 blockade immunotherapy. Nature Cancer,. DOI: 10.1038/s43018-019-0003-0 |
3. Abu Aboud O, Chen CH, Senapedis W, Baloglu E, Argueta C, Weiss RH. (2016)
Dual and Specific Inhibition of NAMPT and PAK4 By KPT-9274 Decreases Kidney Cancer Growth. Mol Cancer Ther, 15 (9): 2119-29. [PMID:27390344] |
4. Baloglu E, Shacham S, Senapedis W, Mccauley D, Landesnam Y, Golan G, Shechter S. (2015)
Substituted benzofuranyl and benzoxazolyl compounds and uses thereof. Patent number: WO2015003166A1. Assignee: Karyopharm Therapeutics Inc.. Priority date: 03/07/2013. Publication date: 08/01/2015. |
5. Rane C, Senapedis W, Baloglu E, Landesman Y, Crochiere M, Das-Gupta S, Minden A. (2017)
A novel orally bioavailable compound KPT-9274 inhibits PAK4, and blocks triple negative breast cancer tumor growth. Sci Rep, 7: 42555. [PMID:28198380] |
6. Sampath D, Zabka TS, Misner DL, O'Brien T, Dragovich PS. (2015)
Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) as a therapeutic strategy in cancer. Pharmacol Ther, 151: 16-31. [PMID:25709099] |
7. Takao S, Chien W, Madan V, Lin DC, Ding LW, Sun QY, Mayakonda A, Sudo M, Xu L, Chen Y et al.. (2018)
Targeting the vulnerability to NAD+ depletion in B-cell acute lymphoblastic leukemia. Leukemia, 32 (3): 616-625. [PMID:28904384] |