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MedKoo Cat#: 563171 | Name: PF-477736
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Description:

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

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.

Chemical Structure

PF-477736
PF-477736
CAS#952021-60-2 (free base)

Theoretical Analysis

MedKoo Cat#: 563171

Name: PF-477736

CAS#: 952021-60-2 (free base)

Chemical Formula: C22H25N7O2

Exact Mass: 419.2070

Molecular Weight: 419.49

Elemental Analysis: C, 62.99; H, 6.01; N, 23.37; O, 7.63

Price and Availability

Size Price Availability Quantity
5mg USD 450.00 2 Weeks
10mg USD 700.00 2 Weeks
25mg USD 1,050.00 2 Weeks
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Related CAS #
1175132-90-7 (HCl) 1071848-28-6 952238-93-6 (?HCl) 1247874-19-6 (2HCl) 952021-60-2 (free base)
Synonym
PF-00477736; PF 00477736; PF00477736; PF-477736; PF 477736; PF477736;
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
InChi Key
NDEXUOWTGYUVGA-LJQANCHMSA-N
InChi Code
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
SMILES Code
O=C(NC1=CC2=C(C3=C1)C(C=NNC3=O)=C(C4=CN(C)N=C4)N2)[C@H](N)C5CCCCC5
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
>3 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:
PF 477736 (PF 00477736) is a potent, selective and ATP-competitive inhibitor of Chk1, with a Ki of 0.49 nM, it is also a Chk2 inhibitor, with a Ki of 47 nM.
In vitro activity:
PF-00477736 was identified as a potent, selective ATP-competitive small-molecule inhibitor that inhibits Chk1 with a K(i) of 0.49 nM. PF-00477736 abrogates cell cycle arrest induced by DNA damage and enhances cytotoxicity of clinically important chemotherapeutic agents, including gemcitabine and carboplatin. Reference: Mol Cancer Ther. 2008 Aug;7(8):2394-404. https://pubmed.ncbi.nlm.nih.gov/18723486/
In vivo activity:
To test the efficacy of PF-477736 in vivo, this study inoculated NOD/SCID mice with A549 isogenic lines subcutaneously and treated with PF-477736 twice on indicated days. LIMD1+/+ tumours were unaffected by PF-477736 treatment in vivo, however this study observed a significant decrease in tumour growth in the LIMD1−/− tumours upon treatment (Figs. 4E and S4A, B). Staining of these tumours with markers for cell proliferation (Ki67, Figs. 4F and S4C) and apoptosis (cleaved caspase-3, Figs. 4G and S4D), revealed that PF-477736 selectivity inhibits proliferation in LIMD1-deficient lung xenografts and increases apoptosis within these tumours, in agreement with in vitro data. Reference: Cell Death Dis. 2021 Nov 11;12(11):1075. https://pubmed.ncbi.nlm.nih.gov/34764236/
Solvent mg/mL mM comments
Solubility
DMF 30.0 71.52
DMSO 67.6 161.18
DMSO:PBS (pH 7.2) (1:1) 0.5 1.19
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 419.49 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.

Recalculate based on batch purity %
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. Ando K, Cázares-Ordoñez V, Makishima M, Yokoyama A, Suenaga Y, Nagase H, Kobayashi S, Kamijo T, Koshinaga T, Wada S. CEP131 Abrogates CHK1 Inhibitor-Induced Replication Defects and Is Associated with Unfavorable Outcome in Neuroblastoma. J Oncol. 2020 Sep 15;2020:2752417. doi: 10.1155/2020/2752417. PMID: 33014050; PMCID: PMC7512061. 2. Blasina A, Hallin J, Chen E, Arango ME, Kraynov E, Register J, Grant S, Ninkovic S, Chen P, Nichols T, O'Connor P, Anderes K. Breaching the DNA damage checkpoint via PF-00477736, a novel small-molecule inhibitor of checkpoint kinase 1. Mol Cancer Ther. 2008 Aug;7(8):2394-404. doi: 10.1158/1535-7163.MCT-07-2391. PMID: 18723486. 3. Davidson K, Grevitt P, Contreras-Gerenas MF, Bridge KS, Hermida M, Shah KM, Mardakheh FK, Stubbs M, Burke R, Casado P, Cutillas PR, Martin SA, Sharp TV. Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypes. Cell Death Dis. 2021 Nov 11;12(11):1075. doi: 10.1038/s41419-021-04355-7. PMID: 34764236; PMCID: PMC8586256. 4. Zhang C, Yan Z, Painter CL, Zhang Q, Chen E, Arango ME, Kuszpit K, Zasadny K, Hallin M, Hallin J, Wong A, Buckman D, Sun G, Qiu M, Anderes K, Christensen JG. PF-00477736 mediates checkpoint kinase 1 signaling pathway and potentiates docetaxel-induced efficacy in xenografts. Clin Cancer Res. 2009 Jul 15;15(14):4630-40. doi: 10.1158/1078-0432.CCR-08-3272. Epub 2009 Jul 7. PMID: 19584159.
In vitro protocol:
1. Ando K, Cázares-Ordoñez V, Makishima M, Yokoyama A, Suenaga Y, Nagase H, Kobayashi S, Kamijo T, Koshinaga T, Wada S. CEP131 Abrogates CHK1 Inhibitor-Induced Replication Defects and Is Associated with Unfavorable Outcome in Neuroblastoma. J Oncol. 2020 Sep 15;2020:2752417. doi: 10.1155/2020/2752417. PMID: 33014050; PMCID: PMC7512061. 2. Blasina A, Hallin J, Chen E, Arango ME, Kraynov E, Register J, Grant S, Ninkovic S, Chen P, Nichols T, O'Connor P, Anderes K. Breaching the DNA damage checkpoint via PF-00477736, a novel small-molecule inhibitor of checkpoint kinase 1. Mol Cancer Ther. 2008 Aug;7(8):2394-404. doi: 10.1158/1535-7163.MCT-07-2391. PMID: 18723486.
In vivo protocol:
1. Davidson K, Grevitt P, Contreras-Gerenas MF, Bridge KS, Hermida M, Shah KM, Mardakheh FK, Stubbs M, Burke R, Casado P, Cutillas PR, Martin SA, Sharp TV. Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypes. Cell Death Dis. 2021 Nov 11;12(11):1075. doi: 10.1038/s41419-021-04355-7. PMID: 34764236; PMCID: PMC8586256. 2. Zhang C, Yan Z, Painter CL, Zhang Q, Chen E, Arango ME, Kuszpit K, Zasadny K, Hallin M, Hallin J, Wong A, Buckman D, Sun G, Qiu M, Anderes K, Christensen JG. PF-00477736 mediates checkpoint kinase 1 signaling pathway and potentiates docetaxel-induced efficacy in xenografts. Clin Cancer Res. 2009 Jul 15;15(14):4630-40. doi: 10.1158/1078-0432.CCR-08-3272. Epub 2009 Jul 7. PMID: 19584159.
1: Smith HL, Willmore E, Prendergast L, Curtin NJ. ATR, CHK1 and WEE1 inhibitors cause homologous recombination repair deficiency to induce synthetic lethality with PARP inhibitors. Br J Cancer. 2024 Jul 4. doi: 10.1038/s41416-024-02745-0. Epub ahead of print. PMID: 38965423. 2: Marcelino TP, Fala AM, da Silva MM, Souza-Melo N, Malvezzi AM, Klippel AH, Zoltner M, Padilla-Mejia N, Kosto S, Field MC, Burle-Caldas GA, Teixeira SMR, Couñago RM, Massirer KB, Schenkman S. Identification of inhibitors for the transmembrane Trypanosoma cruzi eIF2α kinase relevant for parasite proliferation. J Biol Chem. 2023 Jul;299(7):104857. doi: 10.1016/j.jbc.2023.104857. Epub 2023 May 23. PMID: 37230387; PMCID: PMC10300260. 3: Saha S, Rundle S, Kotsopoulos IC, Begbie J, Howarth R, Pappworth IY, Mukhopadhyay A, Kucukmetin A, Marchbank KJ, Curtin N. Determining the Potential of DNA Damage Response (DDR) Inhibitors in Cervical Cancer Therapy. Cancers (Basel). 2022 Sep 1;14(17):4288. doi: 10.3390/cancers14174288. PMID: 36077823; PMCID: PMC9454916. 4: Singh R, Pokle AV, Ghosh P, Ganeshpurkar A, Swetha R, Singh SK, Kumar A. Pharmacophore-based virtual screening, molecular docking and molecular dynamics simulations study for the identification of LIM kinase-1 inhibitors. J Biomol Struct Dyn. 2023 Aug-Sep;41(13):6089-6103. doi: 10.1080/07391102.2022.2101529. Epub 2022 Jul 21. PMID: 35862656. 5: Zhou L, Pei X, Zhang Y, Ning Y, Li L, Hu X, Chalasani SL, Sharma K, Nkwocha J, Yu J, Bandyopadhyay D, Sebti SM, Grant S. Chk1 Inhibition Potently Blocks STAT3 Tyrosine705 Phosphorylation, DNA-Binding Activity, and Activation of Downstream Targets in Human Multiple Myeloma Cells. Mol Cancer Res. 2022 Mar 1;20(3):456-467. doi: 10.1158/1541-7786.MCR-21-0366. PMID: 34782371; PMCID: PMC8898301. 6: Davidson K, Grevitt P, Contreras-Gerenas MF, Bridge KS, Hermida M, Shah KM, Mardakheh FK, Stubbs M, Burke R, Casado P, Cutillas PR, Martin SA, Sharp TV. Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypes. Cell Death Dis. 2021 Nov 11;12(11):1075. doi: 10.1038/s41419-021-04355-7. PMID: 34764236; PMCID: PMC8586256. 7: Ando K, Cázares-Ordoñez V, Makishima M, Yokoyama A, Suenaga Y, Nagase H, Kobayashi S, Kamijo T, Koshinaga T, Wada S. CEP131 Abrogates CHK1 Inhibitor- Induced Replication Defects and Is Associated with Unfavorable Outcome in Neuroblastoma. J Oncol. 2020 Sep 15;2020:2752417. doi: 10.1155/2020/2752417. PMID: 33014050; PMCID: PMC7512061. 8: Choi C, Cho WK, Park S, Shin SW, Park W, Kim H, Choi DH. Checkpoint Kinase 1 (CHK1) Inhibition Enhances the Sensitivity of Triple-Negative Breast Cancer Cells to Proton Irradiation via Rad51 Downregulation. Int J Mol Sci. 2020 Apr 13;21(8):2691. doi: 10.3390/ijms21082691. PMID: 32294924; PMCID: PMC7215565. 9: Smith HL, Prendergast L, Curtin NJ. Exploring the Synergy between PARP and CHK1 Inhibition in Matched BRCA2 Mutant and Corrected Cells. Cancers (Basel). 2020 Apr 4;12(4):878. doi: 10.3390/cancers12040878. PMID: 32260355; PMCID: PMC7226483. 10: Salah E, Chatterjee D, Beltrami A, Tumber A, Preuss F, Canning P, Chaikuad A, Knaus P, Knapp S, Bullock AN, Mathea S. Lessons from LIMK1 enzymology and their impact on inhibitor design. Biochem J. 2019 Nov 15;476(21):3197-3209. doi: 10.1042/BCJ20190517. PMID: 31652302; PMCID: PMC6835155. 11: Homma H, Nojima H, Kaida A, Miura M. Induction of endomitosis-like event in HeLa cells following CHK1 inhibitor treatment. Biochem Biophys Res Commun. 2019 Dec 3;520(2):492-497. doi: 10.1016/j.bbrc.2019.09.046. Epub 2019 Oct 11. PMID: 31610912. 12: Erber J, Steiner JD, Isensee J, Lobbes LA, Toschka A, Beleggia F, Schmitt A, Kaiser RWJ, Siedek F, Persigehl T, Hucho T, Reinhardt HC. Dual Inhibition of GLUT1 and the ATR/CHK1 Kinase Axis Displays Synergistic Cytotoxicity in KRAS-Mutant Cancer Cells. Cancer Res. 2019 Oct 1;79(19):4855-4868. doi: 10.1158/0008-5472.CAN-18-3959. Epub 2019 Aug 12. PMID: 31405847. 13: Schuler F, Afreen S, Manzl C, Häcker G, Erlacher M, Villunger A. Checkpoint kinase 1 is essential for fetal and adult hematopoiesis. EMBO Rep. 2019 Aug;20(8):e47026. doi: 10.15252/embr.201847026. Epub 2019 Jun 17. PMID: 31379128; PMCID: PMC6680171. 14: Ando K, Nakamura Y, Nagase H, Nakagawara A, Koshinaga T, Wada S, Makishima M. Co-Inhibition of the DNA Damage Response and CHK1 Enhances Apoptosis of Neuroblastoma Cells. Int J Mol Sci. 2019 Jul 29;20(15):3700. doi: 10.3390/ijms20153700. PMID: 31362335; PMCID: PMC6696225. 15: Mani C, Pai S, Papke CM, Palle K, Gmeiner WH. Thymineless Death by the Fluoropyrimidine Polymer F10 Involves Replication Fork Collapse and Is Enhanced by Chk1 Inhibition. Neoplasia. 2018 Dec;20(12):1236-1245. doi: 10.1016/j.neo.2018.10.006. Epub 2018 Nov 12. PMID: 30439567; PMCID: PMC6232621. 16: Meng Y, Chen CW, Yung MMH, Sun W, Sun J, Li Z, Li J, Li Z, Zhou W, Liu SS, Cheung ANY, Ngan HYS, Braisted JC, Kai Y, Peng W, Tzatsos A, Li Y, Dai Z, Zheng W, Chan DW, Zhu W. DUOXA1-mediated ROS production promotes cisplatin resistance by activating ATR-Chk1 pathway in ovarian cancer. Cancer Lett. 2018 Aug 1;428:104-116. doi: 10.1016/j.canlet.2018.04.029. Epub 2018 Apr 26. PMID: 29704517; PMCID: PMC7474466. 17: 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. PMID: 29441438. 18: Doerr F, George J, Schmitt A, Beleggia F, Rehkämper T, Hermann S, Walter V, Weber JP, Thomas RK, Wittersheim M, Büttner R, Persigehl T, Reinhardt HC. Targeting a non-oncogene addiction to the ATR/CHK1 axis for the treatment of small cell lung cancer. Sci Rep. 2017 Nov 14;7(1):15511. doi: 10.1038/s41598-017-15840-5. PMID: 29138515; PMCID: PMC5686113. 19: 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. PMID: 27449089; PMCID: PMC5288228. 20: 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. PMID: 26542114; PMCID: PMC4635624.