WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H206989
CAS#: 1234015-54-3 (2HCl)
Description: Prexasertib, also know LY2606368, is a small molecule checkpoint kinase inhibitor that causes DNA double-strand breaks, which results in apoptosis. Prexasertib is mainly active against CHEK1, with minor activity against CHEK2. Preclinical studies have shown that prexasertib induces DNA damage and tumor cell apoptosis in monotherapy. Prexasertib may also potentiate the cytotoxicity of DNA-damaging agents and reverse tumor cell resistance to chemotherapeutic agents.
Hodoodo Cat#: H206989
Name: Prexasertib HCl
CAS#: 1234015-54-3 (2HCl)
Chemical Formula: C18H21Cl2N7O2
Exact Mass: 0.00
Molecular Weight: 438.310
Elemental Analysis: C, 49.33; H, 4.83; Cl, 16.18; N, 22.37; O, 7.30
Related CAS #: 1234015-54-3 (2HCl) 1234015-55-4 (mesylate) 1234015-58-7 (2 mesylate) 1234015-52-1 (free base) 1234015-57-6 (mesylate hydrate) 2100300-72-7 (lactate hydrate) 2781996-46-9 (lactate)
Synonym: Prexasertib HCl; Prexasertib dihydrochloride; LY2606368 HCl; LY-2606368 HCl; LY 2606368 HCl;
IUPAC/Chemical Name: 5-((5-(2-(3-aminopropoxy)-6-methoxyphenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile dihydrochloride
InChi Key: KMEIPKXRCJTZBZ-UHFFFAOYSA-N
InChi Code: InChI=1S/C18H19N7O2.2ClH/c1-26-14-4-2-5-15(27-7-3-6-19)18(14)13-8-16(25-24-13)23-17-11-21-12(9-20)10-22-17;;/h2,4-5,8,10-11H,3,6-7,19H2,1H3,(H2,22,23,24,25);2*1H
SMILES Code: N#CC1=NC=C(NC2=NNC(C3=C(OC)C=CC=C3OCCCN)=C2)N=C1.[H]Cl.[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 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:
| Biological target: | Prexasertib dihydrochloride (LY2606368 dihydrochloride) is an ATP-competitive second-generation checkpoint kinase 1 (CHK1) inhibitor with a Ki of 0.9 nM and an IC50 of |
| In vitro activity: | Five pediatric cancer cell lines representing different childhood sarcomas – A673 (Ewing’s sarcoma); MG-63 (osteosarcoma); RD (embryonal rhabdomyosarcoma [eRMS]); and Rh41 and SJCRH30 (alveolar RMS [aRMS]) – were analyzed for changes in cell signaling following in vitro treatment with prexasertib. Reduction in CHK1 autophosphorylation at S296 indicated that kinase activity was diminished following 24h of treatment in all cell lines evaluated (Fig. 1A). Interestingly, WEE1, a downstream effector of CHK1 and a key modulator of the G2-M checkpoint following DNA damage, was readily detected by immunoblot in SJCRH30 and Rh41 but not in the other 3 cell lines evaluated; decreased phosphorylation of WEE1 in both aRMS cell lines further demonstrated prexasertib-mediated CHK1 inhibition (Fig. 1A). Furthermore, CDK1, CDK2, and CDC25A/C protein levels were relatively unchanged following prexasertib treatment in all cell lines evaluated with the exception of SJCRH30, in which an increase in both CDK2 and CDC25A total protein was noted (Supplementary Fig. S2). Reference: Clin Cancer Res. 2019 Apr 1; 25(7): 2278–2289. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445779/ |
| In vivo activity: | In this work, plasma, tumor and brain ECF disposition of prexasertib were described in mice bearing G3MB and NTB mice receiving a single dose of prexasertib (10 mg/kq, SQ) using cerebral microdialysis and pharmacokinetic modeling. The CNS penetration of prexasertib in tumor-bearing mice was characterized by a mean Kp,uu = 0.17, and was statistically greater than that observed in NTB mice (Kp.uu = 0.09, p-value = 0.04). Pharmacodynamic studies were further performed in tumor-bearing mice to characterize the dynamics of markers of prexasertib efficacy. The increases of nuclear pCHK1 S345 and pH2Ax levels in tumor tissues after a single dose of prexasertib (20 mg/kg, IV) confirmed a treatment-induced target engagement, and thus, an adequate CNS penetration of the CHK1 inhibitor. These results support further preclinical and clinical investigation in treating adult and pediatric CNS malignancies. Reference: Eur J Pharm Sci. 2020 Jan 15; 142: 105106. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925336/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 12.5 | 28.52 |
The following data is based on the product molecular weight 438.31 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. Branigan TB, Kozono D, Schade AE, Deraska P, Rivas HG, Sambel L, Reavis HD, Shapiro GI, D'Andrea AD, DeCaprio JA. MMB-FOXM1-driven premature mitosis is required for CHK1 inhibitor sensitivity. Cell Rep. 2021 Mar 2;34(9):108808. doi: 10.1016/j.celrep.2021.108808. PMID: 33657372; PMCID: PMC7970065. 2. Lowery CD, Dowless M, Renschler M, Blosser W, VanWye AB, Stephens JR, Iversen PW, Lin AB, Beckmann RP, Krytska K, Cole KA, Maris JM, Hawkins DS, Rubin BP, Kurmasheva RT, Houghton PJ, Gorlick R, Kolb EA, Kang MH, Reynolds CP, Erickson SW, Teicher BA, Smith MA, Stancato LF. Broad Spectrum Activity of the Checkpoint Kinase 1 Inhibitor Prexasertib as a Single Agent or Chemopotentiator Across a Range of Preclinical Pediatric Tumor Models. Clin Cancer Res. 2019 Apr 1;25(7):2278-2289. doi: 10.1158/1078-0432.CCR-18-2728. Epub 2018 Dec 18. PMID: 30563935; PMCID: PMC6445779. 3. Campagne O, Davis A, Maharaj AR, Zhong B, Stripay J, Farmer D, Roussel MF, Stewart CF. CNS penetration and pharmacodynamics of the CHK1 inhibitor prexasertib in a mouse Group 3 medulloblastoma model. Eur J Pharm Sci. 2020 Jan 15;142:105106. doi: 10.1016/j.ejps.2019.105106. Epub 2019 Oct 25. PMID: 31669383; PMCID: PMC6925336. 4. King C, Diaz HB, McNeely S, Barnard D, Dempsey J, Blosser W, Beckmann R, Barda D, Marshall MS. LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms. Mol Cancer Ther. 2015 Sep;14(9):2004-13. doi: 10.1158/1535-7163.MCT-14-1037. Epub 2015 Jul 3. PMID: 26141948. |
| In vitro protocol: | 1. Branigan TB, Kozono D, Schade AE, Deraska P, Rivas HG, Sambel L, Reavis HD, Shapiro GI, D'Andrea AD, DeCaprio JA. MMB-FOXM1-driven premature mitosis is required for CHK1 inhibitor sensitivity. Cell Rep. 2021 Mar 2;34(9):108808. doi: 10.1016/j.celrep.2021.108808. PMID: 33657372; PMCID: PMC7970065. 2. Lowery CD, Dowless M, Renschler M, Blosser W, VanWye AB, Stephens JR, Iversen PW, Lin AB, Beckmann RP, Krytska K, Cole KA, Maris JM, Hawkins DS, Rubin BP, Kurmasheva RT, Houghton PJ, Gorlick R, Kolb EA, Kang MH, Reynolds CP, Erickson SW, Teicher BA, Smith MA, Stancato LF. Broad Spectrum Activity of the Checkpoint Kinase 1 Inhibitor Prexasertib as a Single Agent or Chemopotentiator Across a Range of Preclinical Pediatric Tumor Models. Clin Cancer Res. 2019 Apr 1;25(7):2278-2289. doi: 10.1158/1078-0432.CCR-18-2728. Epub 2018 Dec 18. PMID: 30563935; PMCID: PMC6445779. |
| In vivo protocol: | 1. Campagne O, Davis A, Maharaj AR, Zhong B, Stripay J, Farmer D, Roussel MF, Stewart CF. CNS penetration and pharmacodynamics of the CHK1 inhibitor prexasertib in a mouse Group 3 medulloblastoma model. Eur J Pharm Sci. 2020 Jan 15;142:105106. doi: 10.1016/j.ejps.2019.105106. Epub 2019 Oct 25. PMID: 31669383; PMCID: PMC6925336. 2. King C, Diaz HB, McNeely S, Barnard D, Dempsey J, Blosser W, Beckmann R, Barda D, Marshall MS. LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms. Mol Cancer Ther. 2015 Sep;14(9):2004-13. doi: 10.1158/1535-7163.MCT-14-1037. Epub 2015 Jul 3. PMID: 26141948. |
1: Giudice E, Huang TT, Nair JR, Zurcher G, McCoy A, Nousome D, Radke MR, Swisher EM, Lipkowitz S, Ibanez K, Donohue D, Malys T, Lee MJ, Redd B, Levy E, Rastogi S, Sato N, Trepel JB, Lee JM. The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial. Nat Commun. 2024 Mar 30;15(1):2805. doi: 10.1038/s41467-024-47215-6. PMID: 38555285; PMCID: PMC10981752.
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3: Moore KN, Hong DS, Patel MR, Pant S, Ulahannan SV, Jones S, Meric-Bernstam F, Wang JS, Aljumaily R, Hamilton EP, Wittchen ES, Wang X, Lin AB, Bendell JC. A Phase 1b Trial of Prexasertib in Combination with Standard-of-Care Agents in Advanced or Metastatic Cancer. Target Oncol. 2021 Sep;16(5):569-589. doi: 10.1007/s11523-021-00835-0. Epub 2021 Sep 24. PMID: 34559360.
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5: Ostergaard J, Jonart LM, Ebadi M, Koppenhafer SL, Gordon DJ, Gordon PM. Preclinical efficacy of prexasertib in acute lymphoblastic leukemia. Br J Haematol. 2021 Sep;194(6):1094-1098. doi: 10.1111/bjh.17610. Epub 2021 Jun 7. PMID: 34096630; PMCID: PMC8504167.
6: Byers LA, Navarro A, Schaefer E, Johnson M, Özgüroğlu M, Han JY, Bondarenko I, Cicin I, Dragnev KH, Abel A, Wang X, McNeely S, Hynes S, Lin AB, Forster M. A Phase II Trial of Prexasertib (LY2606368) in Patients With Extensive-Stage Small-Cell Lung Cancer. Clin Lung Cancer. 2021 Nov;22(6):531-540. doi: 10.1016/j.cllc.2021.04.005. Epub 2021 Apr 24. PMID: 34034991.
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15: Nair J, Huang TT, Murai J, Haynes B, Steeg PS, Pommier Y, Lee JM. Resistance to the CHK1 inhibitor prexasertib involves functionally distinct CHK1 activities in BRCA wild-type ovarian cancer. Oncogene. 2020 Aug;39(33):5520-5535. doi: 10.1038/s41388-020-1383-4. Epub 2020 Jul 9. PMID: 32647134; PMCID: PMC7426265.
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20: Blosser WD, Dempsey JA, McNulty AM, Rao X, Ebert PJ, Lowery CD, Iversen PW, Webster YW, Donoho GP, Gong X, Merzoug FF, Buchanan S, Boehnke K, Yu C, You XT, Beckmann RP, Wu W, McNeely SC, Lin AB, Martinez R. A pan-cancer transcriptome analysis identifies replication fork and innate immunity genes as modifiers of response to the CHK1 inhibitor prexasertib. Oncotarget. 2020 Jan 21;11(3):216-236. doi: 10.18632/oncotarget.27400. PMID: 32076484; PMCID: PMC6980627.
Wu WH, Bonnet S, Shimauchi T, Toro V, Grobs Y, Romanet C, Bourgeois A, Vitry G, Omura J, Tremblay E, Nadeau V, Orcholski M, Breuils-Bonnet S, Martineau S, Ferraro P, Potus F, Paulin R, Provencher S, Boucherat O. Potential for inhibition of checkpoint kinases 1/2 in pulmonary fibrosis and secondary pulmonary hypertension. Thorax. 2021 Jul 5:thoraxjnl-2021-217377. doi: 10.1136/thoraxjnl-2021-217377. Epub ahead of print. PMID: 34226205.
