Original: KPT-9274 1643913-93-2, stock more than 100g

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Description: KPT-9274, also known as PAK4-IN-1, is a potent, selective and dual PAK4/NAMPT inhibitor. KPT-9274 interferences with PAK4/NAMPT signaling pathways, which results in reduction of G2-M transit as well as induction of apoptosis and decrease in cell invasion and migration in several human RCC cell lines. Mechanistic studies demonstrate that inhibition of the PAK4 pathway by KPT-9274 attenuates nuclear β-catenin as well as the Wnt/β-catenin targets cyclin D1 and c-Myc. KPT-9274 demonstrated the expected on-target effects in this mouse model. KPT-9274 is being evaluated in a phase I human clinical trial in solid tumors and lymphomas, which will allow this data to be rapidly translated into the clinic for the treatment of RCC.

Name: KPT-9274 

CAS#: 1643913-93-2 

Chemical Formula: C35H29F3N4O3 

Exact Mass: 610.2192 

Molecular Weight: 610.6372 

Elemental Analysis: C, 68.84; H, 4.79; F, 9.33; N, 9.18; O, 7.86

Synonym: KPT-9274; KPT9274; KPT 9274; PAK4-IN-1; PAK4-IN 1; PAK4-IN1.

IUPAC/Chemical Name: (1Z,2E)-3-(6-aminopyridin-2-yl)-N-((5-(4-(4,4-difluoropiperidine-1-carbonyl)phenyl)-7-(4-fluorophenyl)benzofuran-2-yl)methyl)acrylimidic acid

InChi Key: KXGUHCDGIDAEIP-OUKQBFOZSA-N

InChi Code: InChI=1S/C35H29F3N4O3/c36-27-10-8-23(9-11-27)30-20-25(22-4-6-24(7-5-22)34(44)42-16-14-35(37,38)15-17-42)18-26-19-29(45-33(26)30)21-40-32(43)13-12-28-2-1-3-31(39)41-28/h1-13,18-20H,14-17,21H2,(H2,39,41)(H,40,43)/b13-12+

SMILES Code: OC(/C=C/C1=NC(N)=CC=C1)=N\CC2=CC3=CC(C4=CC=C(C(N5CCC(F)(F)CC5)=O)C=C4)=CC(C6=CC=C(F)C=C6)=C3O2

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

Harmonized System Code: 293490

ADDITIONAL INFORMATION

Upon administration, KPT-9274 allosterically binds to, destabilizes and causes degradation of PAK4. This inhibits PAK4-mediated signaling, induces cell death in, and inhibits the proliferation of PAK4-overexpressing tumor cells. In addition, KPT-9274 binds to and inhibits the activity of NAMPT. This depletes cellular NAD and inhibits NAD-dependent enzymes, both of which are needed for rapid cell proliferation; this results in tumor cell death in NAMPT-overexpressing cancer cells. PAK4, a serine/threonine kinase and member of the PAK family of proteins upregulated in various cancer cell types, regulates cell motility, proliferation and survival. NAMPT, an enzyme that is responsible for maintaining the intracellular NAD pool, plays a key role in the regulation of cellular metabolism and has cytokine-like activities. NAMPT is often overexpressed in a variety of cancers and metabolic disorders and tumor cells rely on NAMPT activity for their NAD supply.

REFERENCES

1: Rane C, Senapedis W, Baloglu E, Landesman Y, Crochiere M, Das-Gupta S, Minden A. A novel orally bioavailable compound KPT-9274 inhibits PAK4, and blocks triple negative breast cancer tumor growth. Sci Rep. 2017 Feb 15;7:42555. doi: 10.1038/srep42555. PubMed PMID: 28198380.

2: Fulciniti M, Martinez-Lopez J, Senapedis W, Oliva S, Bandi RL, Amodio N, Xu Y, Szalat RL, Gulla A, Samur MK, Roccaro A, Linares M, Cea M, Baloglu E, Argueta C, Landesman Y, Shacham S, Liu S, Schenone M, Wu SL, Karger B, Prabhala R, Anderson KC, Munshi NC. Functional role and therapeutic targeting of p21-associated kinase 4 (PAK4) in multiple myeloma. Blood. 2017 Jan 17. pii: blood-2016-06-724831. doi: 10.1182/blood-2016-06-724831. [Epub ahead of print] PubMed PMID: 28096095.

3: Aboukameel A, Muqbil I, Senapedis W, Baloglu E, Landesman Y, Shacham S, Kauffman M, Philip PA, Mohammad RM, Azmi AS. Novel p21-Activated Kinase 4 (PAK4) Allosteric Modulators Overcome Drug Resistance and Stemness in Pancreatic Ductal Adenocarcinoma. Mol Cancer Ther. 2017 Jan;16(1):76-87. doi: 10.1158/1535-7163.MCT-16-0205. PubMed PMID: 28062705; PubMed Central PMCID: PMC5221563.

4: Abu Aboud O, Chen CH, Senapedis W, Baloglu E, Argueta C, Weiss RH. Dual and Specific Inhibition of NAMPT and PAK4 By KPT-9274 Decreases Kidney Cancer Growth. Mol Cancer Ther. 2016 Sep;15(9):2119-29. doi: 10.1158/1535-7163.MCT-16-0197. PubMed PMID: 27390344; PubMed Central PMCID: PMC5010932.