PF-477736
PF-477736, also known as PF-00477736, is a potent CHK1 inhibitor with potential chemopotentiation activity. PF-477736 inhibits chk1, an ATP-dependent serine-threonine kinase that is a key component in the DNA replication-monitoring S/G2 checkpoint system. By overriding the last checkpoint defense against DNA damaging agent-induced lethal damage, chk1 inhibitor PF-477736 may potentiate the antitumor efficacy of various chemotherapeutic agents against tumor cells with intrinsic checkpoint defects.
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Chemical Information
| Name | PF-477736 |
|---|---|
| Iupac Chemical Name | (2R)-2-Amino-2-cyclohexyl-N-[2-(1-methyl-1H-pyrazol-4-yl)-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl]-acetamide |
| Synonyms | PF-00477736; PF 00477736; PF00477736; PF-477736; PF 477736; PF477736; |
| Molecular Formula | C22H25N7O2 |
| Molecular Weight | 419.48 |
| Smile | O=C(NC1=CC2=C(C3=C1)C(C=NNC3=O)=C(C4=CN(C)N=C4)N2)[C@H](N)C5CCCCC5 |
| InChiKey | NDEXUOWTGYUVGA-LJQANCHMSA-N |
| InChi | InChI=1S/C22H25N7O2/c1-29-11-13(9-25-29)20-16-10-24-28-21(30)15-7-14(8-17(27-20)18(15)16)26-22(31)19(23)12-5-3-2-4-6-12/h7-12,19,27H,2-6,23H2,1H3,(H,26,31)(H,28,30)/t19-/m1/s1 |
| CAS Number | 952021-60-2 |
| Related CAS |
Ordering Information
| Packaging | Price | Availability | Purity | Shipping Time |
|---|---|---|---|---|
| Bulk | Enquiry | Enquiry | Enquiry |
| Formulation | Solid powder |
|---|---|
| Purity | 98% Min. |
| Storage | 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 |
| Handling | |
| 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. |
| HS Code |
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| Mechanism | |
| Cell study | |
| Animal study | |
| Clinical study |
1: Restelli V, Lupi M, Vagni M, Chilà R, Bertoni F, Damia G, Carrassa L. Combining Ibrutinib with Chk1 Inhibitors Synergistically Targets Mantle Cell Lymphoma Cell Lines. Target Oncol. 2018 Apr;13(2):235-245. doi: 10.1007/s11523-018-0553-6. PubMed PMID: 29441438.
2: Prince EW, Balakrishnan I, Shah M, Mulcahy Levy JM, Griesinger AM, Alimova I, Harris PS, Birks DK, Donson AM, Davidson N, Remke M, Taylor MD, Handler MH, Foreman NK, Venkataraman S, Vibhakar R. Checkpoint kinase 1 expression is an adverse prognostic marker and therapeutic target in MYC-driven medulloblastoma. Oncotarget. 2016 Aug 16;7(33):53881-53894. doi: 10.18632/oncotarget.10692. PubMed PMID: 27449089; PubMed Central PMCID: PMC5288228.
3: Iacobucci I, Di Rorà AG, Falzacappa MV, Agostinelli C, Derenzini E, Ferrari A, Papayannidis C, Lonetti A, Righi S, Imbrogno E, Pomella S, Venturi C, Guadagnuolo V, Cattina F, Ottaviani E, Abbenante MC, Vitale A, Elia L, Russo D, Zinzani PL, Pileri S, Pelicci PG, Martinelli G. In vitro and in vivo single-agent efficacy of checkpoint kinase inhibition in acute lymphoblastic leukemia. J Hematol Oncol. 2015 Nov 5;8:125. doi: 10.1186/s13045-015-0206-5. PubMed PMID: 26542114; PubMed Central PMCID: PMC4635624.
4: Restelli V, Chilà R, Lupi M, Rinaldi A, Kwee I, Bertoni F, Damia G, Carrassa L. Characterization of a mantle cell lymphoma cell line resistant to the Chk1 inhibitor PF-00477736. Oncotarget. 2015 Nov 10;6(35):37229-40. doi: 10.18632/oncotarget.5954. PubMed PMID: 26439697; PubMed Central PMCID: PMC4741926.
5: Kim MK, James J, Annunziata CM. Topotecan synergizes with CHEK1 (CHK1) inhibitor to induce apoptosis in ovarian cancer cells. BMC Cancer. 2015 Mar 28;15:196. doi: 10.1186/s12885-015-1231-z. PubMed PMID: 25884494; PubMed Central PMCID: PMC4379550.
6: Derenzini E, Agostinelli C, Imbrogno E, Iacobucci I, Casadei B, Brighenti E, Righi S, Fuligni F, Ghelli Luserna Di Rorà A, Ferrari A, Martinelli G, Pileri S, Zinzani PL. Constitutive activation of the DNA damage response pathway as a novel therapeutic target in diffuse large B-cell lymphoma. Oncotarget. 2015 Mar 30;6(9):6553-69. PubMed PMID: 25544753; PubMed Central PMCID: PMC4466634.
7: Güster JD, Weissleder SV, Busch CJ, Kriegs M, Petersen C, Knecht R, Dikomey E, Rieckmann T. The inhibition of PARP but not EGFR results in the radiosensitization of HPV/p16-positive HNSCC cell lines. Radiother Oncol. 2014 Dec;113(3):345-51. doi: 10.1016/j.radonc.2014.10.011. Epub 2014 Nov 10. PubMed PMID: 25467050.
8: Nguyen T, Hawkins E, Kolluri A, Kmieciak M, Park H, Lin H, Grant S. Synergism between bosutinib (SKI-606) and the Chk1 inhibitor (PF-00477736) in highly imatinib-resistant BCR/ABL⁺ leukemia cells. Leuk Res. 2015 Jan;39(1):65-71. doi: 10.1016/j.leukres.2014.10.009. Epub 2014 Nov 11. PubMed PMID: 25465126; PubMed Central PMCID: PMC4413916.
9: Chilà R, Basana A, Lupi M, Guffanti F, Gaudio E, Rinaldi A, Cascione L, Restelli V, Tarantelli C, Bertoni F, Damia G, Carrassa L. Combined inhibition of Chk1 and Wee1 as a new therapeutic strategy for mantle cell lymphoma. Oncotarget. 2015 Feb 20;6(5):3394-408. PubMed PMID: 25428911; PubMed Central PMCID: PMC4413661.
10: Liu Y, Kwiatkowski DJ. Combined CDKN1A/TP53 mutation in bladder cancer is a therapeutic target. Mol Cancer Ther. 2015 Jan;14(1):174-82. doi: 10.1158/1535-7163.MCT-14-0622-T. Epub 2014 Oct 27. PubMed PMID: 25349305; PubMed Central PMCID: PMC4297264.
11: Sarmento LM, Póvoa V, Nascimento R, Real G, Antunes I, Martins LR, Moita C, Alves PM, Abecasis M, Moita LF, Parkhouse RM, Meijerink JP, Barata JT. CHK1 overexpression in T-cell acute lymphoblastic leukemia is essential for proliferation and survival by preventing excessive replication stress. Oncogene. 2015 Jun 4;34(23):2978-90. doi: 10.1038/onc.2014.248. Epub 2014 Aug 18. PubMed PMID: 25132270.
12: Bryant C, Rawlinson R, Massey AJ. Chk1 inhibition as a novel therapeutic strategy for treating triple-negative breast and ovarian cancers. BMC Cancer. 2014 Aug 7;14:570. doi: 10.1186/1471-2407-14-570. PubMed PMID: 25104095; PubMed Central PMCID: PMC4137066.
13: Al-Ejeh F, Pajic M, Shi W, Kalimutho M, Miranda M, Nagrial AM, Chou A, Biankin AV, Grimmond SM; Australian Pancreatic Cancer Genome Initiative, Brown MP, Khanna KK. Gemcitabine and CHK1 inhibition potentiate EGFR-directed radioimmunotherapy against pancreatic ductal adenocarcinoma. Clin Cancer Res. 2014 Jun 15;20(12):3187-97. doi: 10.1158/1078-0432.CCR-14-0048. Epub 2014 May 16. PubMed PMID: 24838526.
14: Sankunny M, Parikh RA, Lewis DW, Gooding WE, Saunders WS, Gollin SM. Targeted inhibition of ATR or CHEK1 reverses radioresistance in oral squamous cell carcinoma cells with distal chromosome arm 11q loss. Genes Chromosomes Cancer. 2014 Feb;53(2):129-43. doi: 10.1002/gcc.22125. Epub 2013 Nov 25. PubMed PMID: 24327542; PubMed Central PMCID: PMC4216593.
15: Busch CJ, Kriegs M, Laban S, Tribius S, Knecht R, Petersen C, Dikomey E, Rieckmann T. HPV-positive HNSCC cell lines but not primary human fibroblasts are radiosensitized by the inhibition of Chk1. Radiother Oncol. 2013 Sep;108(3):495-9. doi: 10.1016/j.radonc.2013.06.035. Epub 2013 Aug 7. PubMed PMID: 23932155.
16: Fang DD, Cao J, Jani JP, Tsaparikos K, Blasina A, Kornmann J, Lira ME, Wang J, Jirout Z, Bingham J, Zhu Z, Gu Y, Los G, Hostomsky Z, Vanarsdale T. Combined gemcitabine and CHK1 inhibitor treatment induces apoptosis resistance in cancer stem cell-like cells enriched with tumor spheroids from a non-small cell lung cancer cell line. Front Med. 2013 Dec;7(4):462-76. doi: 10.1007/s11684-013-0270-6. Epub 2013 Jul 2. PubMed PMID: 23820871.
17: Chilà R, Celenza C, Lupi M, Damia G, Carrassa L. Chk1-Mad2 interaction: a crosslink between the DNA damage checkpoint and the mitotic spindle checkpoint. Cell Cycle. 2013 Apr 1;12(7):1083-90. doi: 10.4161/cc.24090. Epub 2013 Mar 1. PubMed PMID: 23454898; PubMed Central PMCID: PMC3646864.
18: Carrassa L, Chilà R, Lupi M, Ricci F, Celenza C, Mazzoletti M, Broggini M, Damia G. Combined inhibition of Chk1 and Wee1: in vitro synergistic effect translates to tumor growth inhibition in vivo. Cell Cycle. 2012 Jul 1;11(13):2507-17. doi: 10.4161/cc.20899. Epub 2012 Jul 1. PubMed PMID: 22713237.
19: Ferrao PT, Bukczynska EP, Johnstone RW, McArthur GA. Efficacy of CHK inhibitors as single agents in MYC-driven lymphoma cells. Oncogene. 2012 Mar 29;31(13):1661-72. doi: 10.1038/onc.2011.358. Epub 2011 Aug 15. PubMed PMID: 21841818.
20: Shibata H, Miuma S, Saldivar JC, Huebner K. Response of subtype-specific human breast cancer-derived cells to poly(ADP-ribose) polymerase and checkpoint kinase 1 inhibition. Cancer Sci. 2011 Oct;102(10):1882-8. doi: 10.1111/j.1349-7006.2011.02016.x. Epub 2011 Jul 21. PubMed PMID: 21707865; PubMed Central PMCID: PMC3193851.
Chemical Structure
