PHA-665752 | CAS# 477575-56-7 | c-MET inhibitor

MedKoo Cat#: 202231 | Name: PHA-665752

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Description:

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

PHA665752 is a potent and selective inhibitor of c-Met/HGF/SF (IC50 values are 9, 68, 200, 1400, 3000, 3800 and 6000 nM for MET, Ron, Flk-1, c-abl, FGFR1, EGFR and c-src respectively). PHA-665752 suppresses the hepatocyte growth factor-induced cell proliferation and radioresistance in nasopharyngeal carcinoma cells. PHA-665752 reverses lung premalignancy induced by mutant K-ras. PHA-665752 induced apoptosis of a lung adenocarcinoma cell line derived from Kras(LA1) mice (LKR-13) and a murine lung endothelial cell line (MEC). PHA-665752 inhibited lung tumorigenesis in Kras(LA1) mice and may provide a novel therapeutic approach to the prevention of K-ras-mutant NSCLC.

Chemical Structure

PHA-665752

CAS#477575-56-7

Theoretical Analysis

MedKoo Cat#: 202231

Name: PHA-665752

CAS#: 477575-56-7

Chemical Formula: C32H34Cl2N4O4S

Exact Mass: 640.1678

Molecular Weight: 641.61

Elemental Analysis: C, 59.90; H, 5.34; Cl, 11.05; N, 8.73; O, 9.97; S, 5.00

Price and Availability

Size	Price	Availability
50mg	USD 750.00	2 Weeks
100mg	USD 1,250.00	2 Weeks
200mg	USD 1,950.00	2 Weeks
500mg	USD 2,950.00	2 Weeks
1g	USD 4,250.00	2 Weeks

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Synonym

PHA665752; PHA 665752; PHA 665752

IUPAC/Chemical Name

(R,Z)-5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-(2-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carbonyl)-1H-pyrrol-2-yl)methylene)indolin-2-one

InChi Key

OYONTEXKYJZFHA-SSHUPFPWSA-N

InChi Code

InChI=1S/C32H34Cl2N4O4S/c1-19-29(35-20(2)30(19)32(40)38-14-6-7-21(38)17-37-12-3-4-13-37)16-24-23-15-22(10-11-28(23)36-31(24)39)43(41,42)18-25-26(33)8-5-9-27(25)34/h5,8-11,15-16,21,35H,3-4,6-7,12-14,17-18H2,1-2H3,(H,36,39)/b24-16-/t21-/m1/s1

SMILES Code

O=C1NC2=C(C=C(S(=O)(CC3=C(Cl)C=CC=C3Cl)=O)C=C2)/C1=C/C4=C(C)C(C(N5[C@@H](CN6CCCC6)CCC5)=O)=C(C)N4

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

>5 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

Product Data

Product Data

Instruction

View handling instruction

Biological target:

PHA-665752 is a selective, ATP-competitive, and active-site inhibitor of the catalytic activity of c-Met kinase (Ki=4 nM; IC50=9 nM).

In vitro activity:

The effect of PHA665752 treatment was determined on cell growth, motility and migration, apoptosis, and cell-cycle arrest of TPR-MET-transformed cells. PHA665752 specifically inhibited cell growth in BaF3. TPR-MET cells (IC(50) < 0.06 micromol/L), induced apoptosis and cell cycle arrest. Constitutive cell motility and migration of the BaF3. TPR-MET cells was also inhibited. PHA665752 inhibited specific phosphorylation of TPR-MET as well as phosphorylation of downstream targets of the mammalian target of rapamycin pathway. Reference: Clin Cancer Res. 2005 Mar 15;11(6):2312-9. https://pubmed.ncbi.nlm.nih.gov/15788682/

In vivo activity:

This study shows that treatment with PHA665752 reduced NCI-H69 (small cell lung cancer) and NCI-H441 (non-small cell lung cancer) tumorigenicity in mouse xenografts by 99% and 75%, respectively. Reduction in tumor size was also observed by magnetic resonance imaging of tumors in mice. PHA665752 inhibited c-Met phosphorylation at the autophosphorylation and c-Cbl binding sites in mouse xenografts derived from non-small cell lung cancer cell lines (NCI-H441 and A549) and small cell lung cancer cell line (NCI-H69). Reference: Cancer Res. 2007 Apr 15;67(8):3529-34. https://pubmed.ncbi.nlm.nih.gov/17440059/

	Solvent	mg/mL	mM
Solubility
	DMF	25.0	38.96
	DMF:PBS (pH 7.2) (1:1)	0.5	0.78
	DMSO	56.8	88.51
	Ethanol	1.0	1.56

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 641.61 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. Chen W, Wu S, Huang Y, Zhang T, Dong H, Zheng X, Chen T, Gong X, Liu G, Zhao X. A c-Met Inhibitor Suppresses Osteosarcoma Progression via the ERK1/2 Pathway in Human Osteosarcoma Cells. Onco Targets Ther. 2021 Sep 10;14:4791-4804. doi: 10.2147/OTT.S317122. PMID: 34531665; PMCID: PMC8440230. 2. Ma PC, Schaefer E, Christensen JG, Salgia R. A selective small molecule c-MET Inhibitor, PHA665752, cooperates with rapamycin. Clin Cancer Res. 2005 Mar 15;11(6):2312-9. doi: 10.1158/1078-0432.CCR-04-1708. PMID: 15788682. 3. Puri N, Khramtsov A, Ahmed S, Nallasura V, Hetzel JT, Jagadeeswaran R, Karczmar G, Salgia R. A selective small molecule inhibitor of c-Met, PHA665752, inhibits tumorigenicity and angiogenesis in mouse lung cancer xenografts. Cancer Res. 2007 Apr 15;67(8):3529-34. doi: 10.1158/0008-5472.CAN-06-4416. PMID: 17440059. 4. Christensen JG, Schreck R, Burrows J, Kuruganti P, Chan E, Le P, Chen J, Wang X, Ruslim L, Blake R, Lipson KE, Ramphal J, Do S, Cui JJ, Cherrington JM, Mendel DB. A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo. Cancer Res. 2003 Nov 1;63(21):7345-55. PMID: 14612533.

In vitro protocol:

In vivo protocol:

1. Puri N, Khramtsov A, Ahmed S, Nallasura V, Hetzel JT, Jagadeeswaran R, Karczmar G, Salgia R. A selective small molecule inhibitor of c-Met, PHA665752, inhibits tumorigenicity and angiogenesis in mouse lung cancer xenografts. Cancer Res. 2007 Apr 15;67(8):3529-34. doi: 10.1158/0008-5472.CAN-06-4416. PMID: 17440059. 2. Christensen JG, Schreck R, Burrows J, Kuruganti P, Chan E, Le P, Chen J, Wang X, Ruslim L, Blake R, Lipson KE, Ramphal J, Do S, Cui JJ, Cherrington JM, Mendel DB. A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo. Cancer Res. 2003 Nov 1;63(21):7345-55. PMID: 14612533.

1: Correction for Smolen et al., Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752. Proc Natl Acad Sci U S A. 2024 Jun 18;121(25):e2410435121. doi: 10.1073/pnas.2410435121. Epub 2024 Jun 13. Erratum for: Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2316-21. doi: 10.1073/pnas.0508776103. PMID: 38870064; PMCID: PMC11194582. 2: Yadav AK, Wang S, Shin YM, Jang BC. PHA-665752's Antigrowth and Proapoptotic Effects on HSC-3 Human Oral Cancer Cells. Int J Mol Sci. 2024 Mar 1;25(5):2871. doi: 10.3390/ijms25052871. PMID: 38474118; PMCID: PMC10932316. 3: Redmer T, Schumann E, Peters K, Weidemeier ME, Nowak S, Schroeder HWS, Vidal A, Radbruch H, Lehmann A, Kreuzer-Redmer S, Jürchott K, Radke J. MET receptor serves as a promising target in melanoma brain metastases. Acta Neuropathol. 2024 Feb 22;147(1):44. doi: 10.1007/s00401-024-02694-1. Erratum in: Acta Neuropathol. 2024 Mar 27;147(1):63. doi: 10.1007/s00401-024-02719-9. PMID: 38386085; PMCID: PMC10884227. 4: Liu Y, Yuan Y, Chen T, Xiao H, Zhang X, Zhang F. Identification of aneuploidy-related gene signature to predict survival in head and neck squamous cell carcinomas. Aging (Albany NY). 2023 Nov 20;15(22):13100-13117. doi: 10.18632/aging.205221. Epub 2023 Nov 20. PMID: 37988195; PMCID: PMC10713391. 5: Huang Y, Zhang Y, Zhou Q, Teng Y, Sui M, Zhang F. Combined immune and DDR pathway classifier: A novel pathway-based classification aimed at tailoring personalized therapies for acute myeloid leukemia patients. Comput Biol Med. 2023 Aug;162:107093. doi: 10.1016/j.compbiomed.2023.107093. Epub 2023 May 29. PMID: 37269679. 6: Zhao T, Liu B, Zhang M, Li S, Zhao C, Cheng L. Assessment of alterations in histone modification function and guidance for death risk prediction in cervical cancer patients. Front Genet. 2022 Sep 19;13:1013571. doi: 10.3389/fgene.2022.1013571. PMID: 36199574; PMCID: PMC9527294. 7: Zhao D, Yang Z, Chen C, Zhang Z, Yu Y, Li Z. CXCR4 promotes gefitinib resistance of Huh7 cells by activating the c-Met signaling pathway. FEBS Open Bio. 2021 Nov;11(11):3115-3125. doi: 10.1002/2211-5463.13305. Epub 2021 Oct 19. PMID: 34555268; PMCID: PMC8564344. 8: Chen W, Wu S, Huang Y, Zhang T, Dong H, Zheng X, Chen T, Gong X, Liu G, Zhao X. A c-Met Inhibitor Suppresses Osteosarcoma Progression via the ERK1/2 Pathway in Human Osteosarcoma Cells. Onco Targets Ther. 2021 Sep 10;14:4791-4804. doi: 10.2147/OTT.S317122. PMID: 34531665; PMCID: PMC8440230. 9: Li J, Chu T, Yang M. Oleic acid induces A7r5 cell proliferation and migration associated with increased expression of HGF and p‑p38. Mol Med Rep. 2021 Jul;24(1):484. doi: 10.3892/mmr.2021.12123. Epub 2021 Apr 28. PMID: 33907848; PMCID: PMC8127074. 10: Goodwin JS, Tsai LL, Mwin D, Coutinho de Souza P, Dialani S, Moon JT, Zhang Z, Grant AK, Ahmed M. In vivo detection of distal tumor glycolytic flux stimulated by hepatic ablation in a breast cancer model using hyperpolarized 13C MRI. Magn Reson Imaging. 2021 Jul;80:90-97. doi: 10.1016/j.mri.2021.04.004. Epub 2021 Apr 24. PMID: 33901585; PMCID: PMC8203414. 11: Choi MH, Kim J, Ha JH, Park JU. A selective small-molecule inhibitor of c-Met suppresses keloid fibroblast growth in vitro and in a mouse model. Sci Rep. 2021 Mar 9;11(1):5468. doi: 10.1038/s41598-021-84982-4. PMID: 33750878; PMCID: PMC7943593. 12: Day EK, Zhong Q, Purow B, Lazzara MJ. Data-Driven Computational Modeling Identifies Determinants of Glioblastoma Response to SHP2 Inhibition. Cancer Res. 2021 Apr 15;81(8):2056-2070. doi: 10.1158/0008-5472.CAN-20-1756. Epub 2021 Feb 11. PMID: 33574084; PMCID: PMC8394281. 13: Peng F, Chang W, Sun Q, Xu X, Xie J, Qiu H, Yang Y. HGF alleviates septic endothelial injury by inhibiting pyroptosis via the mTOR signalling pathway. Respir Res. 2020 Aug 14;21(1):215. doi: 10.1186/s12931-020-01480-3. PMID: 32795289; PMCID: PMC7427898. 14: Fujita R, Blot V, Wong E, Stewart C, Lieuw V, Richardson R, Banah A, Villicana J, Timmer A, Coronella J, Newman R, Gymnopoulos M. A novel non-agonist c-Met antibody drug conjugate with superior potency over a c-Met tyrosine kinase inhibitor in c-Met amplified and non-amplified cancers. Cancer Biol Ther. 2020 Jun 2;21(6):549-559. doi: 10.1080/15384047.2020.1737490. Epub 2020 Mar 19. PMID: 32192391; PMCID: PMC7515515. 15: Fu R, Jiang S, Li J, Chen H, Zhang X. Activation of the HGF/c-MET axis promotes lenvatinib resistance in hepatocellular carcinoma cells with high c-MET expression. Med Oncol. 2020 Mar 12;37(4):24. doi: 10.1007/s12032-020-01350-4. PMID: 32166604. 16: Zaky MY, Liu X, Wang T, Wang S, Liu F, Wang D, Wu Y, Zhang Y, Guo D, Sun Q, Li Q, Zhang J, Zhang Y, Dong W, Liu Z, Liu S, Liu H. Dynasore potentiates c-Met inhibitors against hepatocellular carcinoma through destabilizing c-Met. Arch Biochem Biophys. 2020 Feb 15;680:108239. doi: 10.1016/j.abb.2019.108239. Epub 2019 Dec 24. PMID: 31881189. 17: Liao H, Ahmed M, Markezana A, Zeng G, Stechele M, Galun E, Goldberg SN. Thermal Ablation Induces Transitory Metastatic Growth by Means of the STAT3/c-Met Molecular Pathway in an Intrahepatic Colorectal Cancer Mouse Model. Radiology. 2020 Feb;294(2):464-472. doi: 10.1148/radiol.2019191023. Epub 2019 Dec 17. PMID: 31845846; PMCID: PMC6996862. 18: Jung J, Yang K, Kim HJ, Lee YJ, Kim M, Choi YH, Kang JL. RhoA-Dependent HGF and c-Met Mediate Gas6-Induced Inhibition of Epithelial-Mesenchymal Transition, Migration, and Invasion of Lung Alveolar Epithelial Cells. Biomolecules. 2019 Oct 4;9(10):565. doi: 10.3390/biom9100565. PMID: 31590238; PMCID: PMC6843420. 19: Choi W, Lee J, Lee J, Lee SH, Kim S. Hepatocyte Growth Factor Regulates Macrophage Transition to the M2 Phenotype and Promotes Murine Skeletal Muscle Regeneration. Front Physiol. 2019 Jul 25;10:914. doi: 10.3389/fphys.2019.00914. PMID: 31404148; PMCID: PMC6672745. 20: Yoon YJ, Shin HS, Lim JY. A hepatocyte growth factor/MET-induced antiapoptotic pathway protects against radiation-induced salivary gland dysfunction. Radiother Oncol. 2019 Sep;138:9-16. doi: 10.1016/j.radonc.2019.05.012. Epub 2019 May 25. PMID: 31136962.