Prexasertib mesylate | CAS#1234015-55-4 | Chk1 inhibitor

MedKoo Cat#: 206787 | Name: Prexasertib mesylate

Description:

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

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.

Chemical Structure

Prexasertib mesylate

CAS#1234015-55-4 (mesylate)

Theoretical Analysis

MedKoo Cat#: 206787

Name: Prexasertib mesylate

CAS#: 1234015-55-4 (mesylate)

Chemical Formula: C19H23N7O5S

Exact Mass: 0.0000

Molecular Weight: 461.50

Elemental Analysis: C, 49.45; H, 5.02; N, 21.25; O, 17.33; S, 6.95

Price and Availability

Size	Price	Availability
10mg	USD 150.00	Ready to ship
25mg	USD 250.00	Ready to ship
50mg	USD 450.00	Ready to ship
100mg	USD 750.00	Ready to ship
200mg	USD 1,250.00	Ready to Ship
500mg	USD 2,450.00	Ready to Ship
1g	USD 4,250.00	Ready to Ship

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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 mesylate; LY2606368; LY-2606368; LY 2606368.

IUPAC/Chemical Name

2-Pyrazinecarbonitrile, 5-((5-(2-(3-aminopropoxy)-6-methoxyphenyl)-1H-pyrazol-3-yl)amino)-, methanesulfonate

InChi Key

WGCKOJKXQKKLQW-UHFFFAOYSA-N

InChi Code

InChI=1S/C18H19N7O2.CH4O3S/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;1-5(2,3)4/h2,4-5,8,10-11H,3,6-7,19H2,1H3,(H2,22,23,24,25);1H3,(H,2,3,4)

SMILES Code

N#CC1=NC=C(NC2=NNC(C3=C(OC)C=CC=C3OCCCN)=C2)N=C1.CS(=O)(O)=O

Appearance

Yellow 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

>2 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

Certificate of Analysis

View CoA: current batch, Lot#Y7X05M22

View CoA: current batch, Lot#YXM210710

QC Data

View QC data: current batch, Lot#YXM210710

View QC data: current batch, Lot#Y7X05M22

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

Prexasertib inhibits CHK1, CHK2, and RSK1 with IC50s of <1 nM, 8 nM, and 9 nM, respectively.

In vitro activity:

The efficacy of the Checkpoint kinase 1/2 (Chk 1/2) inhibitor prexasertib mesylate in B-/T- cell progenitor acute lymphoblastic leukemia (ALL) was evaluated. Prexasertib reduced the cell viability in a dose and time dependent manner in all treated cell lines. The cytotoxic activity was confirmed by the increment of apoptotic cells (Annexin V/Propidium Iodide staining), by the increase of γH2A.X protein expression and by the activation of different apoptotic markers (Parp-1 and pro-Caspase3 cleavage). Furthermore, the inhibition of Chk1 changed the cell cycle profile. Prexasertib reduced the amount of cells in G1 and G2/M phase while increasing the number of cells in S phase. Reference: Oncotarget. 2016 Aug 16;7(33):53377-53391. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5288194/

In vivo activity:

The antitumor efficacy of LY2606368 was investigated in a syngeneic flank tumor model generated from subcutaneous injection of cells (TKO.mTmG) derived from a GEMM (genetically engineered mouse model) with conditional loss of Trp53, p130, and Rb1 in the neuroendocrine cells of the lung (23, 24). These mice developed tumors that closely resembled human SCLC (small cell lung cancer). Tumor-bearing mice (n = 9 per group) were treated with LY2606368 or vehicle. Within 1 week of the start of treatment with LY2606368, remarkable tumor regression was observed (Fig. 3A; Supplementary Fig. S3B). Of the 9 mice treated with LY2606368 (10 mg/kg, twice daily, days 1–3 of a 7-day cycle; i.e., 60 mg/kg per week), 6 had a complete response (100% reduction) and the other 3 had >75% reduction in tumor volume. The tumor–control ratio at day 12 was 0.02 (P < 0.001). Mice treated with a lower dose of LY2606368 (16 mg/kg, twice daily, day 1 of a 7-day cycle; i.e., 32 mg/kg per week) had stable disease for up to 30 days, with a tumor–control ratio of 0.16 (P < 0.001; Fig. 3A; Supplementary Fig. S3B). In contrast, all vehicle-treated mice (n = 9) experienced rapid tumor progression and were removed from the experiment because of excessive tumor volume within two weeks (Fig. 3A and B; Supplementary Fig. S3B). Reference: Cancer Res. 2017 Jul 15;77(14):3870-3884. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5563854/

	Solvent	mg/mL	mM	comments
Solubility
	DMSO	24.0	52.00

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 461.50 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. Ghelli Luserna Di Rorà A, Iacobucci I, Imbrogno E, Papayannidis C, Derenzini E, Ferrari A, Guadagnuolo V, Robustelli V, Parisi S, Sartor C, Abbenante MC, Paolini S, Martinelli G. Prexasertib, a Chk1/Chk2 inhibitor, increases the effectiveness of conventional therapy in B-/T- cell progenitor acute lymphoblastic leukemia. Oncotarget. 2016 Aug 16;7(33):53377-53391. doi: 10.18632/oncotarget.10535. PMID: 27438145; PMCID: PMC5288194. 2. Brill E, Yokoyama T, Nair J, Yu M, Ahn YR, Lee JM. Prexasertib, a cell cycle checkpoint kinases 1 and 2 inhibitor, increases in vitro toxicity of PARP inhibition by preventing Rad51 foci formation in BRCA wild type high-grade serous ovarian cancer. Oncotarget. 2017 Oct 31;8(67):111026-111040. doi: 10.18632/oncotarget.22195. PMID: 29340034; PMCID: PMC5762302. 3. Zeng L, Nikolaev A, Xing C, Della Manna DL, Yang ES. CHK1/2 Inhibitor Prexasertib Suppresses NOTCH Signaling and Enhances Cytotoxicity of Cisplatin and Radiation in Head and Neck Squamous Cell Carcinoma. Mol Cancer Ther. 2020 Jun;19(6):1279-1288. doi: 10.1158/1535-7163.MCT-19-0946. Epub 2020 May 5. PMID: 32371584. 4. Sen T, Tong P, Stewart CA, Cristea S, Valliani A, Shames DS, Redwood AB, Fan YH, Li L, Glisson BS, Minna JD, Sage J, Gibbons DL, Piwnica-Worms H, Heymach JV, Wang J, Byers LA. CHK1 Inhibition in Small-Cell Lung Cancer Produces Single-Agent Activity in Biomarker-Defined Disease Subsets and Combination Activity with Cisplatin or Olaparib. Cancer Res. 2017 Jul 15;77(14):3870-3884. doi: 10.1158/0008-5472.CAN-16-3409. Epub 2017 May 10. PMID: 28490518; PMCID: PMC5563854.

In vitro protocol:

In vivo protocol:

1. Zeng L, Nikolaev A, Xing C, Della Manna DL, Yang ES. CHK1/2 Inhibitor Prexasertib Suppresses NOTCH Signaling and Enhances Cytotoxicity of Cisplatin and Radiation in Head and Neck Squamous Cell Carcinoma. Mol Cancer Ther. 2020 Jun;19(6):1279-1288. doi: 10.1158/1535-7163.MCT-19-0946. Epub 2020 May 5. PMID: 32371584. 2. Sen T, Tong P, Stewart CA, Cristea S, Valliani A, Shames DS, Redwood AB, Fan YH, Li L, Glisson BS, Minna JD, Sage J, Gibbons DL, Piwnica-Worms H, Heymach JV, Wang J, Byers LA. CHK1 Inhibition in Small-Cell Lung Cancer Produces Single-Agent Activity in Biomarker-Defined Disease Subsets and Combination Activity with Cisplatin or Olaparib. Cancer Res. 2017 Jul 15;77(14):3870-3884. doi: 10.1158/0008-5472.CAN-16-3409. Epub 2017 May 10. PMID: 28490518; PMCID: PMC5563854.

1: Brill E, Yokoyama T, Nair J, Yu M, Ahn YR, Lee JM. Prexasertib, a cell cycle checkpoint kinases 1 and 2 inhibitor, increases in vitro toxicity of PARP inhibition by preventing Rad51 foci formation in BRCA wild type high-grade serous ovarian cancer. Oncotarget. 2017 Oct 31;8(67):111026-111040. doi: 10.18632/oncotarget.22195. PMID: 29340034; PMCID: PMC5762302. 2:Ghelli Luserna Di Rorà A, Iacobucci I, Imbrogno E, Papayannidis C, Derenzini E, Ferrari A, Guadagnuolo V, Robustelli V, Parisi S, Sartor C, Abbenante MC, Paolini S, Martinelli G. Prexasertib, a Chk1/Chk2 inhibitor, increases the effectiveness of conventional therapy in B-/T- cell progenitor acute lymphoblastic leukemia. Oncotarget. 2016 Aug 16;7(33):53377-53391. doi: 10.18632/oncotarget.10535. PMID: 27438145; PMCID: PMC5288194. 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. 4: Do KT, Kochupurakkal B, Kelland S, de Jonge A, Hedglin J, Powers A, Quinn N, Gannon C, Vuong L, Parmar K, Lazaro JB, D'Andrea AD, Shapiro GI. Phase 1 Combination Study of the CHK1 Inhibitor Prexasertib and the PARP Inhibitor Olaparib in High-grade Serous Ovarian Cancer and Other Solid Tumors. Clin Cancer Res. 2021 Sep 1;27(17):4710-4716. doi: 10.1158/1078-0432.CCR-21-1279. Epub 2021 Jun 15. PMID: 34131002. 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. 7: Cash T, Fox E, Liu X, Minard CG, Reid JM, Scheck AC, Weigel BJ, Wetmore C. A phase 1 study of prexasertib (LY2606368), a CHK1/2 inhibitor, in pediatric patients with recurrent or refractory solid tumors, including CNS tumors: A report from the Children's Oncology Group Pediatric Early Phase Clinical Trials Network (ADVL1515). Pediatr Blood Cancer. 2021 Sep;68(9):e29065. doi: 10.1002/pbc.29065. Epub 2021 Apr 21. PMID: 33881209; PMCID: PMC9090141. 8: Liu C, Xie J, Wu W, Wang M, Chen W, Idres SB, Rong J, Deng LW, Khan SA, Wu J. Automated synthesis of prexasertib and derivatives enabled by continuous-flow solid-phase synthesis. Nat Chem. 2021 May;13(5):451-457. doi: 10.1038/s41557-021-00662-w. Epub 2021 Apr 19. PMID: 33875818; PMCID: PMC8054510. 9: Do KT, Manuszak C, Thrash E, Giobbie-Hurder A, Hu J, Kelland S, Powers A, de Jonge A, Shapiro GI, Severgnini M. Immune modulating activity of the CHK1 inhibitor prexasertib and anti-PD-L1 antibody LY3300054 in patients with high- grade serous ovarian cancer and other solid tumors. Cancer Immunol Immunother. 2021 Oct;70(10):2991-3000. doi: 10.1007/s00262-021-02910-x. Epub 2021 Mar 20. PMID: 33745032. 10: Yang ES, Deutsch E, Mehmet A, Fayette J, Tao Y, Nabell L, Spencer SA, Wang XA, Spoljoric EA, Zhang W, Hynes SM, Decker RL, Lin AKB, William WN Jr. A Phase 1b trial of prexasertib in combination with chemoradiation in patients with locally advanced head and neck squamous cell carcinoma. Radiother Oncol. 2021 Apr;157:203-209. doi: 10.1016/j.radonc.2021.01.032. Epub 2021 Feb 9. PMID: 33577866. 11: Hong DS, Moore KN, Bendell JC, Karp DD, Wang JS, Ulahannan SV, Jones S, Wu W, Donoho GP, Ding Y, Capen A, Wang X, Bence Lin A, Patel MR. Preclinical Evaluation and Phase Ib Study of Prexasertib, a CHK1 Inhibitor, and Samotolisib (LY3023414), a Dual PI3K/mTOR Inhibitor. Clin Cancer Res. 2021 Apr 1;27(7):1864-1874. doi: 10.1158/1078-0432.CCR-20-3242. Epub 2021 Jan 25. PMID: 33495309. 12: Chaudhary R, Slebos RJC, Song F, McCleary-Sharpe KP, Masannat J, Tan AC, Wang X, Amaladas N, Wu W, Hall GE, Conejo-Garcia JR, Hernandez-Prera JC, Chung CH. Effects of checkpoint kinase 1 inhibition by prexasertib on the tumor immune microenvironment of head and neck squamous cell carcinoma. Mol Carcinog. 2021 Feb;60(2):138-150. doi: 10.1002/mc.23275. Epub 2020 Dec 30. PMID: 33378592; PMCID: PMC7856233. 13: Lee KJ, Wright G, Bryant H, Wiggins LA, Schuler M, Gassman NR. EGFR signaling promotes resistance to CHK1 inhibitor prexasertib in triple negative breast cancer. Cancer Drug Resist. 2020 Dec 5;3(4):980-991. doi: 10.20517/cdr.2020.73. PMID: 35582228; PMCID: PMC8992551. 14: Lampert EJ, Cimino-Mathews A, Lee JS, Nair J, Lee MJ, Yuno A, An D, Trepel JB, Ruppin E, Lee JM. Clinical outcomes of prexasertib monotherapy in recurrent BRCA wild-type high-grade serous ovarian cancer involve innate and adaptive immune responses. J Immunother Cancer. 2020 Jul;8(2):e000516. doi: 10.1136/jitc-2019-000516. PMID: 32709712; PMCID: PMC7380948. 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. 16: Morimoto Y, Takada K, Takeuchi O, Watanabe K, Hirohara M, Hamamoto T, Masuda Y. Bcl-2/Bcl-xL inhibitor navitoclax increases the antitumor effect of Chk1 inhibitor prexasertib by inducing apoptosis in pancreatic cancer cells via inhibition of Bcl-xL but not Bcl-2. Mol Cell Biochem. 2020 Sep;472(1-2):187-198. doi: 10.1007/s11010-020-03796-6. Epub 2020 Jun 21. PMID: 32567031. 17: Evangelisti G, Barra F, Moioli M, Sala P, Stigliani S, Gustavino C, Costantini S, Ferrero S. Prexasertib: an investigational checkpoint kinase inhibitor for the treatment of high-grade serous ovarian cancer. Expert Opin Investig Drugs. 2020 Aug;29(8):779-792. doi: 10.1080/13543784.2020.1783238. Epub 2020 Jun 25. PMID: 32539469. 18: Gatti-Mays ME, Karzai FH, Soltani SN, Zimmer A, Green JE, Lee MJ, Trepel JB, Yuno A, Lipkowitz S, Nair J, McCoy A, Lee JM. A Phase II Single Arm Pilot Study of the CHK1 Inhibitor Prexasertib (LY2606368) in BRCA Wild-Type, Advanced Triple-Negative Breast Cancer. Oncologist. 2020 Dec;25(12):1013-e1824. doi: 10.1634/theoncologist.2020-0491. Epub 2020 Jun 24. PMID: 32510664; PMCID: PMC7938394. 19: Zeng L, Nikolaev A, Xing C, Della Manna DL, Yang ES. CHK1/2 Inhibitor Prexasertib Suppresses NOTCH Signaling and Enhances Cytotoxicity of Cisplatin and Radiation in Head and Neck Squamous Cell Carcinoma. Mol Cancer Ther. 2020 Jun;19(6):1279-1288. doi: 10.1158/1535-7163.MCT-19-0946. Epub 2020 May 5. PMID: 32371584. 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.