KPT-9274 | PAK4-IN-1 |CAS#1643913-93-2 | PAK4/NAMPT inhibitor

MedKoo Cat#: 206767 | Name: KPT-9274

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Padnarsertib, also known as KPT-9274 and 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.

Chemical Structure

KPT-9274

CAS#1643913-93-2 (free base)

Theoretical Analysis

MedKoo Cat#: 206767

Name: KPT-9274

CAS#: 1643913-93-2 (free base)

Chemical Formula: C35H29F3N4O3

Exact Mass: 610.2192

Molecular Weight: 610.64

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

Price and Availability

Size	Price	Availability
5mg	USD 150.00	Ready to ship
10mg	USD 250.00	Ready to ship
25mg	USD 550.00	Ready to ship
50mg	USD 950.00	Ready to ship
100mg	USD 1,650.00	Ready to ship
200mg	USD 2,950.00	Ready to ship

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Related CAS #

1643913-93-2 (free base) Padnarsertib HCl

Synonym

KPT-9274; KPT9274; KPT 9274; PAK4-IN-1; PAK4-IN 1; PAK4-IN1; Padnarsertib.

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

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

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).

HS Tariff Code

2934.99.9001

More Info

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.

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#XPR70221

QC Data

View QC data: current batch, Lot#XPR70221

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

KPT-9274 is a dual PAK4/Nicotinamide phosphoribosyltransferase (NAMPT) inhibitor, with IC50s less than 100 and 120 nM, respectively.

In vitro activity:

The inhibition of NAMPT using KPT-9274 leads to a dose- and time-dependent decrease in mitochondrial activity and an increase in apoptosis. Moreover, KPT-9274 diminished the self-renewal capacity of acute myeloid leukemia (AML) cells in vitro after replating, demonstrating a continual decrease in colony formation after the treatment was discontinued. KPT-9274 diminishes NAD+ levels concomitant with impaired mitochondrial and non-mitochondrial respiration. In addition, later-onset apoptosis is reversed with NAD+ supplementation, suggesting that AML cell survival is sensitive to NAD+ levels reduced by KPT-9274 treatment. Reference: Blood Adv. 2019 Feb 12;3(3):242-255. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373756/

In vivo activity:

To assess the effect of KPT-9274 in an in vivo disseminated model of acute myeloid leukemia (AML), luciferase-positive MV4-11 cells were engrafted by tail vein into NOD/SCID IL2rγ−/− (NSG) mice. One week after engraftment, mice were dosed once daily via oral gavage with 150 mg/kg of KPT-9274 (n = 7) or vehicle control (n = 6) (Figure 6A). KPT-9274 resulted in improved overall survival (median survival of 82 days vs 30 days; P = .0005) (Figure 6B). At the study’s end point, disease burden in different organs was assessed. Bone marrow from KPT-9274–treated mice harbored significantly less human CD45+/CD33+ cells vs vehicle control (P = .0025) (Figure 6C). In addition, KPT-9274–treated marrow differentials showed increased differentiation with fewer blasts and larger numbers of late-stage myeloid cells vs vehicle-treated mice (Figure 6D, top panels). Decreased tumor infiltration was observed in the spleens of inhibitor-treated mice (Figure 6D, bottom panel). Reference: Blood Adv. 2019 Feb 12;3(3):242-255. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373756/

	Solvent	mg/mL	mM
Solubility
	DMSO	100.0	163.76
	Ethanol	100.0	163.76

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 610.64 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Cordover E, Wei J, Patel C, Shan NL, Gionco J, Sargsyan D, Wu R, Cai L, Kong AN, Jacinto E, Minden A. KPT-9274, an Inhibitor of PAK4 and NAMPT, Leads to Downregulation of mTORC2 in Triple Negative Breast Cancer Cells. Chem Res Toxicol. 2020 Feb 17;33(2):482-491. doi: 10.1021/acs.chemrestox.9b00376. Epub 2020 Jan 9. PMID: 31876149. 2. Mitchell SR, Larkin K, Grieselhuber NR, Lai TH, Cannon M, Orwick S, Sharma P, Asemelash Y, Zhang P, Goettl VM, Beaver L, Mims A, Puduvalli VK, Blachly JS, Lehman A, Harrington B, Henderson S, Breitbach JT, Williams KE, Dong S, Baloglu E, Senapedis W, Kirschner K, Sampath D, Lapalombella R, Byrd JC. Selective targeting of NAMPT by KPT-9274 in acute myeloid leukemia. Blood Adv. 2019 Feb 12;3(3):242-255. doi: 10.1182/bloodadvances.2018024182. PMID: 30692102; PMCID: PMC6373756.

In vitro protocol:

In vivo protocol:

1. Mitchell SR, Larkin K, Grieselhuber NR, Lai TH, Cannon M, Orwick S, Sharma P, Asemelash Y, Zhang P, Goettl VM, Beaver L, Mims A, Puduvalli VK, Blachly JS, Lehman A, Harrington B, Henderson S, Breitbach JT, Williams KE, Dong S, Baloglu E, Senapedis W, Kirschner K, Sampath D, Lapalombella R, Byrd JC. Selective targeting of NAMPT by KPT-9274 in acute myeloid leukemia. Blood Adv. 2019 Feb 12;3(3):242-255. doi: 10.1182/bloodadvances.2018024182. PMID: 30692102; PMCID: PMC6373756.

1: Li Y, Lu Q, Xie C, Yu Y, Zhang A. Recent advances on development of p21-activated kinase 4 inhibitors as anti-tumor agents. Front Pharmacol. 2022 Aug 29;13:956220. doi: 10.3389/fphar.2022.956220. PMID: 36105226; PMCID: PMC9465411. 2: Khan HY, Uddin MH, Balasubramanian SK, Sulaiman N, Iqbal M, Chaker M, Aboukameel A, Li Y, Senapedis W, Baloglu E, Mohammad RM, Zonder J, Azmi AS. PAK4 and NAMPT as Novel Therapeutic Targets in Diffuse Large B-Cell Lymphoma, Follicular Lymphoma, and Mantle Cell Lymphoma. Cancers (Basel). 2021 Dec 29;14(1):160. doi: 10.3390/cancers14010160. PMID: 35008323; PMCID: PMC8750170. 3: Subedi A, Liu Q, Ayyathan DM, Sharon D, Cathelin S, Hosseini M, Xu C, Voisin V, Bader GD, D'Alessandro A, Lechman ER, Dick JE, Minden MD, Wang JCY, Chan SM. Nicotinamide phosphoribosyltransferase inhibitors selectively induce apoptosis of AML stem cells by disrupting lipid homeostasis. Cell Stem Cell. 2021 Oct 7;28(10):1851-1867.e8. doi: 10.1016/j.stem.2021.06.004. Epub 2021 Jul 21. PMID: 34293334. 4: Sharma P, Xu J, Williams K, Easley M, Elder JB, Lonser R, Lang FF, Lapalombella R, Sampath D, Puduvalli VK. Inhibition of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the nicotinamide adenine dinucleotide (NAD) salvage pathway, to target glioma heterogeneity through mitochondrial oxidative stress. Neuro Oncol. 2022 Feb 1;24(2):229-244. doi: 10.1093/neuonc/noab175. PMID: 34260721; PMCID: PMC8804900. 5: Mpilla GB, Uddin MH, Al-Hallak MN, Aboukameel A, Li Y, Kim SH, Beydoun R, Dyson G, Baloglu E, Senapedis WT, Landesman Y, Wagner KU, Viola NT, El-Rayes BF, Philip PA, Mohammad RM, Azmi AS. PAK4-NAMPT Dual Inhibition Sensitizes Pancreatic Neuroendocrine Tumors to Everolimus. Mol Cancer Ther. 2021 Oct;20(10):1836-1845. doi: 10.1158/1535-7163.MCT-20-1105. Epub 2021 Jul 12. PMID: 34253597; PMCID: PMC8492493. 6: Mitchell S, Zhang P, Cannon M, Beaver L, Lehman A, Harrington B, Sampath D, Byrd JC, Lapalombella R. Anti-tumor NAMPT inhibitor, KPT-9274, mediates gender- dependent murine anemia and nephrotoxicity by regulating SIRT3-mediated SOD deacetylation. J Hematol Oncol. 2021 Jun 29;14(1):101. doi: 10.1186/s13045-021-01107-0. PMID: 34187548; PMCID: PMC8243474. 7: Zhang P, Brinton LT, Williams K, Sher S, Orwick S, Tzung-Huei L, Mims AS, Coss CC, Kulp SK, Youssef Y, Chan WK, Mitchell S, Mustonen A, Cannon M, Phillips H, Lehman AM, Kauffman T, Beaver L, Canfield D, Grieselhuber NR, Alinari L, Sampath D, Yan P, Byrd JC, Blachly JS, Lapalombella R. Targeting DNA Damage Repair Functions of Two Histone Deacetylases, HDAC8 and SIRT6, Sensitizes Acute Myeloid Leukemia to NAMPT Inhibition. Clin Cancer Res. 2021 Apr 15;27(8):2352-2366. doi: 10.1158/1078-0432.CCR-20-3724. Epub 2021 Feb 4. PMID: 33542077; PMCID: PMC8054771. 8: Qasim SL, Sierra L, Shuck R, Kurenbekova L, Patel TD, Rajapakshe K, Wulff J, Nakahata K, Kim HR, Landesman Y, Unger TJ, Coarfa C, Yustein JT. p21-activated kinases as viable therapeutic targets for the treatment of high-risk Ewing sarcoma. Oncogene. 2021 Feb;40(6):1176-1190. doi: 10.1038/s41388-020-01600-9. Epub 2021 Jan 7. PMID: 33414491. 9: Dasgupta A, Sierra L, Tsang SV, Kurenbekova L, Patel T, Rajapakse K, Shuck RL, Rainusso N, Landesman Y, Unger T, Coarfa C, Yustein JT. Targeting PAK4 Inhibits Ras-Mediated Signaling and Multiple Oncogenic Pathways in High-Risk Rhabdomyosarcoma. Cancer Res. 2021 Jan 1;81(1):199-212. doi: 10.1158/0008-5472.CAN-20-0854. Epub 2020 Nov 9. PMID: 33168646; PMCID: PMC7878415. 10: Neggers JE, Jacquemyn M, Dierckx T, Kleinstiver BP, Thibaut HJ, Daelemans D. enAsCas12a Enables CRISPR-Directed Evolution to Screen for Functional Drug Resistance Mutations in Sequences Inaccessible to SpCas9. Mol Ther. 2021 Jan 6;29(1):208-224. doi: 10.1016/j.ymthe.2020.09.025. Epub 2020 Sep 20. PMID: 33002419; PMCID: PMC7791016. 11: Trott JF, Aboud OA, McLaughlin B, Anderson KL, Modiano JF, Kim K, Jen KY, Senapedis W, Chang H, Landesman Y, Baloglu E, Pili R, Weiss RH. Anti-Cancer Activity of PAK4/NAMPT Inhibitor and Programmed Cell Death Protein-1 Antibody in Kidney Cancer. Kidney360. 2020 May 28;1(5):376-388. doi: 10.34067/kid.0000282019. PMID: 35224510; PMCID: PMC8809296. 12: Asawa RR, Danchik C, Zakharov A, Chen Y, Voss T, Jadhav A, Wallace DP, Trott JF, Weiss RH, Simeonov A, Martinez NJ. A high-throughput screening platform for Polycystic Kidney Disease (PKD) drug repurposing utilizing murine and human ADPKD cells. Sci Rep. 2020 Mar 6;10(1):4203. doi: 10.1038/s41598-020-61082-3. Erratum in: Sci Rep. 2022 Oct 13;12(1):17185. PMID: 32144367; PMCID: PMC7060218. 13: Abril-Rodriguez G, Torrejon DY, Liu W, Zaretsky JM, Nowicki TS, Tsoi J, Puig-Saus C, Baselga-Carretero I, Medina E, Quist MJ, Garcia AJ, Senapedis W, Baloglu E, Kalbasi A, Cheung-Lau G, Berent-Maoz B, Comin-Anduix B, Hu-Lieskovan S, Wang CY, Grasso CS, Ribas A. PAK4 inhibition improves PD-1 blockade immunotherapy. Nat Cancer. 2020;1(1):46-58. doi: 10.1038/s43018-019-0003-0. Epub 2019 Dec 9. Erratum in: Nat Cancer. 2020 Feb;1(2):264. PMID: 34368780; PMCID: PMC8340852. 14: Cordover E, Wei J, Patel C, Shan NL, Gionco J, Sargsyan D, Wu R, Cai L, Kong AN, Jacinto E, Minden A. KPT-9274, an Inhibitor of PAK4 and NAMPT, Leads to Downregulation of mTORC2 in Triple Negative Breast Cancer Cells. Chem Res Toxicol. 2020 Feb 17;33(2):482-491. doi: 10.1021/acs.chemrestox.9b00376. Epub 2020 Jan 9. PMID: 31876149; PMCID: PMC9316853. 15: Mpilla G, Aboukameel A, Muqbil I, Kim S, Beydoun R, Philip PA, Mohammad RM, Kamgar M, Shidham V, Senapedis W, Baloglu E, Li J, Dyson G, Xue Y, El-Rayes B, Azmi AS. PAK4-NAMPT Dual Inhibition as a Novel Strategy for Therapy Resistant Pancreatic Neuroendocrine Tumors. Cancers (Basel). 2019 Nov 29;11(12):1902. doi: 10.3390/cancers11121902. PMID: 31795447; PMCID: PMC6966587. 16: Arowosegbe MA, Amusan OT, Adeola SA, Adu OB, Akinola IA, Ogungbe BF, Omotuyi OI, Saibu GM, Ogunleye AJ, Kanmodi RI, Lugbe NE, Ogunmola OJ, Ajayi DC, Ogun SO, Oyende FO, Bello AO, Ishola PG, Obasieke PE. Kaempferol as a Potential PAK4 Inhibitor in Triple Negative Breast Cancer: Extra Precision Glide Docking and Free Energy Calculation. Curr Drug Discov Technol. 2020;17(5):682-695. doi: 10.2174/1570163816666190823135948. PMID: 31441728. 17: Mitchell SR, Larkin K, Grieselhuber NR, Lai TH, Cannon M, Orwick S, Sharma P, Asemelash Y, Zhang P, Goettl VM, Beaver L, Mims A, Puduvalli VK, Blachly JS, Lehman A, Harrington B, Henderson S, Breitbach JT, Williams KE, Dong S, Baloglu E, Senapedis W, Kirschner K, Sampath D, Lapalombella R, Byrd JC. Selective targeting of NAMPT by KPT-9274 in acute myeloid leukemia. Blood Adv. 2019 Feb 12;3(3):242-255. doi: 10.1182/bloodadvances.2018024182. PMID: 30692102; PMCID: PMC6373756. 18: Li N, Lopez MA, Linares M, Kumar S, Oliva S, Martinez-Lopez J, Xu L, Xu Y, Perini T, Senapedis W, Baloglu E, Shammas MA, Hunter Z, Anderson KC, Treon SP, Munshi NC, Fulciniti M. Dual PAK4-NAMPT Inhibition Impacts Growth and Survival, and Increases Sensitivity to DNA-Damaging Agents in Waldenström Macroglobulinemia. Clin Cancer Res. 2019 Jan 1;25(1):369-377. doi: 10.1158/1078-0432.CCR-18-1776. Epub 2018 Sep 11. PMID: 30206161; PMCID: PMC6320280. 19: Neggers JE, Kwanten B, Dierckx T, Noguchi H, Voet A, Bral L, Minner K, Massant B, Kint N, Delforge M, Vercruysse T, Baloglu E, Senapedis W, Jacquemyn M, Daelemans D. Target identification of small molecules using large-scale CRISPR-Cas mutagenesis scanning of essential genes. Nat Commun. 2018 Feb 5;9(1):502. doi: 10.1038/s41467-017-02349-8. PMID: 29402884; PMCID: PMC5799254. 20: Takao S, Chien W, Madan V, Lin DC, Ding LW, Sun QY, Mayakonda A, Sudo M, Xu L, Chen Y, Jiang YY, Gery S, Lill M, Park E, Senapedis W, Baloglu E, Müschen M, Koeffler HP. Targeting the vulnerability to NAD+ depletion in B-cell acute lymphoblastic leukemia. Leukemia. 2018 Mar;32(3):616-625. doi: 10.1038/leu.2017.281. Epub 2017 Sep 14. PMID: 28904384.