WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 406181
CAS#: 942425-68-5 (HCl)
Description: PHA-767491, also known as CAY10572, is a potent, ATP-competitive dual cdc7/cdk9 inhibitor (IC50 values are 10 and 34 nM respectively) that prevents initiation of DNA replication. PHA-767491 Suppresses Hepatocarcinoma Synergistically with 5-Fluorouracil. PHA-767491 in combination with 5-FU exhibited much stronger cytotoxicity and induced significant apoptosis manifested by remarkably increased caspase 3 activation and poly(ADP-Ribose) polymerase fragmentation in HCC cells. PHA-767491 directly counteracted the 5-FU-induced phosphorylation of Chk1, a substrate of Cdc7; and decreased the expression of the anti-apoptotic protein myeloid leukemia cell 1, a downstream target of Cdk9.
MedKoo Cat#: 406181
Name: PHA-767491 HCl
CAS#: 942425-68-5 (HCl)
Chemical Formula: C12H12ClN3O
Molecular Weight: 249.7
Elemental Analysis: C, 57.72; H, 4.84; Cl, 14.20; N, 16.83; O, 6.41.
Synonym: PHA767491; PHA-767491; PHA 767491; CAY10572; CAY-10572; CAY 10572.
IUPAC/Chemical Name: 1,5,6,7-Tetrahydro-2-(4-pyridinyl)-4 H -pyrrolo[3,2- c ]pyridin-4-one hydrochloride
InChi Key: IMVNFURYBZMFDZ-UHFFFAOYSA-N
InChi Code: InChI=1S/C12H11N3O.ClH/c16-12-9-7-11(8-1-4-13-5-2-8)15-10(9)3-6-14-12;/h1-2,4-5,7,15H,3,6H2,(H,14,16);1H
SMILES Code: O=C1C2=C(NC(C3=CC=NC=C3)=C2)CCN1.[H]Cl
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 DMSOr.
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
|Biological target:||PHA-767491 hydrochloride is a dual Cdc7/Cdk9 inhibitor, with IC50s of 10 nM and 34 nM, respectively.|
|In vitro activity:||To formulate a range of working concentrations for PHA-767491, the effect of different concentrations of PHA-767491 on lymphocytes from C57BL/6 mice stimulated were examined by plate-bound anti-CD3 antibodies. Incubation with PHA-767491 suppressed CD25 expression on the stimulated lymphocytes in a dose-dependent manner (Figure S1A). It was sought to confirm that the application of PHA-767491 indeed suppressed the activities of its main targets, the protein kinases Cdc7 and Cdk9. Indeed, the amount of phosphorylation of MCM2 from unstimulated Jurkat cells and other cell lines decreased in response to PHA-767491 treatment (Figure S2), reflecting reduced Cdc7 activity. The dual kinase inhibitor PHA-767491 suppressed phosphorylation of both RNAPII and MCM2 in both Jurkat cells (Figure 2A) and OT-I CTL (Figure 2B). PHA-767491 also showed a stronger inhibitory effect on RNAPII phosphorylation than LDC067. Lastly, PHA-767491 potently inhibited the upregulation of surface markers of T cell activation, secretion of most cytokines, and antigen-driven proliferation. Reference: Front Immunol. 2019; 10: 1718. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6670834/|
|In vivo activity:||TBD|
|Solvent||Max Conc. mg/mL||Max Conc. mM|
The following data is based on the product molecular weight 249.7 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. Erbayraktar Z, Alural B, Erbayraktar RS, Erkan EP. Cell division cycle 7-kinase inhibitor PHA-767491 hydrochloride suppresses glioblastoma growth and invasiveness. Cancer Cell Int. 2016 Nov 18;16:88. doi: 10.1186/s12935-016-0364-8. PMID: 27891063; PMCID: PMC5116134. 2. Chen EW, Tay NQ, Brzostek J, Gascoigne NRJ, Rybakin V. A Dual Inhibitor of Cdc7/Cdk9 Potently Suppresses T Cell Activation. Front Immunol. 2019 Jul 25;10:1718. doi: 10.3389/fimmu.2019.01718. PMID: 31402912; PMCID: PMC6670834.|
|In vitro protocol:||1. Erbayraktar Z, Alural B, Erbayraktar RS, Erkan EP. Cell division cycle 7-kinase inhibitor PHA-767491 hydrochloride suppresses glioblastoma growth and invasiveness. Cancer Cell Int. 2016 Nov 18;16:88. doi: 10.1186/s12935-016-0364-8. PMID: 27891063; PMCID: PMC5116134. 2. Chen EW, Tay NQ, Brzostek J, Gascoigne NRJ, Rybakin V. A Dual Inhibitor of Cdc7/Cdk9 Potently Suppresses T Cell Activation. Front Immunol. 2019 Jul 25;10:1718. doi: 10.3389/fimmu.2019.01718. PMID: 31402912; PMCID: PMC6670834.|
|In vivo protocol:||TBD|
1: Li W, Zhao XL, Shang SQ, Shen HQ, Chen X. Dual Inhibition of Cdc7 and Cdk9 by PHA-767491 Suppresses Hepatocarcinoma Synergistically with 5-Fluorouracil. Curr Cancer Drug Targets. 2015;15(3):196-204. PubMed PMID: 25643258.
2: Sasi NK, Tiwari K, Soon FF, Bonte D, Wang T, Melcher K, Xu HE, Weinreich M. The potent Cdc7-Dbf4 (DDK) kinase inhibitor XL413 has limited activity in many cancer cell lines and discovery of potential new DDK inhibitor scaffolds. PLoS One. 2014 Nov 20;9(11):e113300. doi: 10.1371/journal.pone.0113300. eCollection 2014. PubMed PMID: 25412417; PubMed Central PMCID: PMC4239038.
3: Poh WT, Chadha GS, Gillespie PJ, Kaldis P, Blow JJ. Xenopus Cdc7 executes its essential function early in S phase and is counteracted by checkpoint-regulated protein phosphatase 1. Open Biol. 2014 Jan 8;4:130138. doi: 10.1098/rsob.130138. PubMed PMID: 24403013; PubMed Central PMCID: PMC3909274.
4: Natoni A, Coyne MR, Jacobsen A, Rainey MD, O'Brien G, Healy S, Montagnoli A, Moll J, O'Dwyer M, Santocanale C. Characterization of a Dual CDC7/CDK9 Inhibitor in Multiple Myeloma Cellular Models. Cancers (Basel). 2013 Jul 24;5(3):901-18. doi: 10.3390/cancers5030901. PubMed PMID: 24202326; PubMed Central PMCID: PMC3795371.
5: Rainey MD, Harhen B, Wang GN, Murphy PV, Santocanale C. Cdc7-dependent and -independent phosphorylation of Claspin in the induction of the DNA replication checkpoint. Cell Cycle. 2013 May 15;12(10):1560-8. doi: 10.4161/cc.24675. Epub 2013 Apr 17. PubMed PMID: 23598722; PubMed Central PMCID: PMC3680535.
6: Liachko NF, McMillan PJ, Guthrie CR, Bird TD, Leverenz JB, Kraemer BC. CDC7 inhibition blocks pathological TDP-43 phosphorylation and neurodegeneration. Ann Neurol. 2013 Jul;74(1):39-52. doi: 10.1002/ana.23870. Epub 2013 Jul 8. PubMed PMID: 23424178; PubMed Central PMCID: PMC3775949.
7: Natoni A, Murillo LS, Kliszczak AE, Catherwood MA, Montagnoli A, Samali A, O'Dwyer M, Santocanale C. Mechanisms of action of a dual Cdc7/Cdk9 kinase inhibitor against quiescent and proliferating CLL cells. Mol Cancer Ther. 2011 Sep;10(9):1624-34. doi: 10.1158/1535-7163.MCT-10-1119. Epub 2011 Jul 18. PubMed PMID: 21768328.
8: Yecies D, Carlson NE, Deng J, Letai A. Acquired resistance to ABT-737 in lymphoma cells that up-regulate MCL-1 and BFL-1. Blood. 2010 Apr 22;115(16):3304-13. doi: 10.1182/blood-2009-07-233304. Epub 2010 Mar 2. PubMed PMID: 20197552; PubMed Central PMCID: PMC2858493.
9: Jackson PK. Stopping replication, at the beginning. Nat Chem Biol. 2008 Jun;4(6):331-2. doi: 10.1038/nchembio0608-331. PubMed PMID: 18488006.
10: Montagnoli A, Valsasina B, Croci V, Menichincheri M, Rainoldi S, Marchesi V, Tibolla M, Tenca P, Brotherton D, Albanese C, Patton V, Alzani R, Ciavolella A, Sola F, Molinari A, Volpi D, Avanzi N, Fiorentini F, Cattoni M, Healy S, Ballinari D, Pesenti E, Isacchi A, Moll J, Bensimon A, Vanotti E, Santocanale C. A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity. Nat Chem Biol. 2008 Jun;4(6):357-65. doi: 10.1038/nchembio.90. Epub 2008 May 11. PubMed PMID: 18469809.