Rabusertib | LY-2603618 | CAS#911222-45-2

MedKoo Cat#: 201794 | Name: Rabusertib (LY2603618)

Description:

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

Rabusertib, also known as LY2603618, is a n inhibitor of the cell cycle checkpoint kinase 2 (chk2) with potential chemopotentiating activity. Rabusertib binds to and inhibits the activity of chk2, which may prevent the repair of DNA caused by DNA-damaging agents, thus potentiating the antitumor efficacies of various chemotherapeutic agents. Chk2, an ATP-dependent serine-threonine kinase, is a key component in the DNA replication-monitoring checkpoint system and is activated by double-stranded breaks (DSBs); activated chk2 is overexpressed by a variety of cancer cell types.

Chemical Structure

Rabusertib (LY2603618)

CAS#911222-45-2

Theoretical Analysis

MedKoo Cat#: 201794

Name: Rabusertib (LY2603618)

CAS#: 911222-45-2

Chemical Formula: C18H22BrN5O3

Exact Mass: 435.0906

Molecular Weight: 436.30

Elemental Analysis: C, 49.55; H, 5.08; Br, 18.31; N, 16.05; O, 11.00

Price and Availability

Size	Price	Availability
10mg	USD 110.00	Ready to ship
25mg	USD 220.00	Ready to ship
50mg	USD 385.00	Ready to ship
100mg	USD 685.00	Ready to ship
200mg	USD 1,150.00	Ready to ship
500mg	USD 2,450.00	Ready to ship

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Related CAS #

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Synonym

LY2603618; LY 2603618; LY-2603618; Rabusertib

IUPAC/Chemical Name

(S)-1-(5-bromo-4-methyl-2-(morpholin-2-ylmethoxy)phenyl)-3-(5-methylpyrazin-2-yl)urea.

InChi Key

SYYBDNPGDKKJDU-ZDUSSCGKSA-N

InChi Code

InChI=1S/C18H22BrN5O3/c1-11-5-16(27-10-13-8-20-3-4-26-13)15(6-14(11)19)23-18(25)24-17-9-21-12(2)7-22-17/h5-7,9,13,20H,3-4,8,10H2,1-2H3,(H2,22,23,24,25)/t13-/m0/s1

SMILES Code

CC1=C(Br)C=C(C(OC[C@@H]2CNCCO2)=C1)NC(NC3=NC=C(N=C3)C)=O

Appearance

White to off-white 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, not in water

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#BBC51225

View CoA: current batch, Lot#BBC60817

QC Data

View QC data: current batch, Lot#BBC60817

View QC data: current batch, Lot# BBC51225

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

Rabusertib (LY2603618) is a potent and selective inhibitor of Chk1 with an IC50 of 7 nM.

In vitro activity:

To further investigate cell death in a larger panel of cell lines and to exclude dose-dependent cell death, this study performed an ApoTox-Glo Triplex assay (Promega) with multiple concentrations of LY2603618/Rabusertib (Fig. 5a and S4c). Sensitive cell lines UM-SCC-22A and UM-SCC-38 both showed a rise in active caspase 3/7, a known marker for apoptosis execution, in relation to an increasing concentration of LY2603618/Rabusertib after 24 h, with a negligible increase of caspase-independent cytotoxicity (Fig. 5a). Reference: Oncogenesis. 2019 Jul; 8(7): 38. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572811/

In vivo activity:

In order to assess the effects on DNA damage response resulting from combining LY2603618 with gemcitabine, mice implanted with Calu-6 tumor xenografts were administered vehicle, 150 mg/kg gemcitabine, 200 mg/kg LY2603618 or gemcitabine plus LY2603618 concurrently. Tumors were removed either 8 or 24 h later and analyzed by immunoblot for phosphorylation of CHK1 serine 345 by ATR, CHK1 serine 296 autophosphorylation and H2AX serine 139 phosphorylation (Fig. 4a, b, c). Although activated by gemcitabine at both 8 and 24 h, CHK1 activity is strongly inhibited by co-administration of LY2603618 for at least 24 h. As shown previously, LY2603618 did not inhibit the phosphorylation of CHK1 on serine 345 by ATR. CHK1 serine 345 phosphorylation increased after 8 h of combination treatment as described previously for other CHK1 inhibitors. In this xenograft model, treatment with gemcitabine alone caused minimal double-stranded DNA breaks as indicated by no increase in pH2AX (S139) levels. However when gemcitabine and LY2603618 are combined, a two-fold increase in pH2AX (S139) was measured in as little as 8 h and further increased nearly four-fold by 24 h, indicating an accumulation of DNA damage in the tumors. Reference: Invest New Drugs. 2016 Feb;34(1):49-60. https://pubmed.ncbi.nlm.nih.gov/26612134/

	Solvent	mg/mL	mM
Solubility
	DMFO	20.4	46.83
	DMF	20.0	45.84
	DMF:PBS (pH 7.2) (1:1)	0.5	1.15

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 436.30 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. van Harten AM, Buijze M, van der Mast R, Rooimans MA, Martens-de Kemp SR, Bachas C, Brink A, Stigter-van Walsum M, Wolthuis RMF, Brakenhoff RH. Targeting the cell cycle in head and neck cancer by Chk1 inhibition: a novel concept of bimodal cell death. Oncogenesis. 2019 Jun 17;8(7):38. doi: 10.1038/s41389-019-0147-x. PMID: 31209198; PMCID: PMC6572811. 2. Zhao J, Niu X, Li X, Edwards H, Wang G, Wang Y, Taub JW, Lin H, Ge Y. Inhibition of CHK1 enhances cell death induced by the Bcl-2-selective inhibitor ABT-199 in acute myeloid leukemia cells. Oncotarget. 2016 Jun 7;7(23):34785-99. doi: 10.18632/oncotarget.9185. PMID: 27166183; PMCID: PMC5085189. 3. King C, Diaz H, Barnard D, Barda D, Clawson D, Blosser W, Cox K, Guo S, Marshall M. Characterization and preclinical development of LY2603618: a selective and potent Chk1 inhibitor. Invest New Drugs. 2014 Apr;32(2):213-26. doi: 10.1007/s10637-013-0036-7. Epub 2013 Oct 10. PMID: 24114124. 4. Barnard D, Diaz HB, Burke T, Donoho G, Beckmann R, Jones B, Barda D, King C, Marshall M. LY2603618, a selective CHK1 inhibitor, enhances the anti-tumor effect of gemcitabine in xenograft tumor models. Invest New Drugs. 2016 Feb;34(1):49-60. doi: 10.1007/s10637-015-0310-y. Epub 2015 Nov 27. PMID: 26612134.

In vitro protocol:

In vivo protocol:

1. King C, Diaz H, Barnard D, Barda D, Clawson D, Blosser W, Cox K, Guo S, Marshall M. Characterization and preclinical development of LY2603618: a selective and potent Chk1 inhibitor. Invest New Drugs. 2014 Apr;32(2):213-26. doi: 10.1007/s10637-013-0036-7. Epub 2013 Oct 10. PMID: 24114124. 2. Barnard D, Diaz HB, Burke T, Donoho G, Beckmann R, Jones B, Barda D, King C, Marshall M. LY2603618, a selective CHK1 inhibitor, enhances the anti-tumor effect of gemcitabine in xenograft tumor models. Invest New Drugs. 2016 Feb;34(1):49-60. doi: 10.1007/s10637-015-0310-y. Epub 2015 Nov 27. PMID: 26612134.

1: Hainley LE, Hughson MS, Narendran A, Smith R, Arthur J, Hayner-Buchan A, Conti DJ, Lehman JM, Friedrich TD. Chk1 and the Host Cell DNA Damage Response as a Potential Antiviral Target in BK Polyomavirus Infection. Viruses. 2021 Jul 13;13(7):1353. doi: 10.3390/v13071353. PMID: 34372559; PMCID: PMC8310304. 2: El-Chaar NN, Smith TE, Shrestha G, Piccolo SR, Harper MK, Van Wagoner RM, Lu Z, Venancio AR, Ireland CM, Bild AH, Moos PJ. Topsentinol L Trisulfate, a Marine Natural Product That Targets Basal-like and Claudin-Low Breast Cancers. Mar Drugs. 2021 Jan 18;19(1):41. doi: 10.3390/md19010041. PMID: 33477536; PMCID: PMC7831112. 3: Xin C, Chao Z, Xian W, Zhonggao W, Tao L. The phosphorylation of CHK1 at Ser345 regulates the phenotypic switching of vascular smooth muscle cells both in vitro and in vivo. Atherosclerosis. 2020 Nov;313:50-59. doi: 10.1016/j.atherosclerosis.2020.09.014. Epub 2020 Sep 24. PMID: 33027721. 4: Ju JQ, Li XH, Pan MH, Xu Y, Sun MH, Xu Y, Sun SC. CHK1 monitors spindle assembly checkpoint and DNA damage repair during the first cleavage of mouse early embryos. Cell Prolif. 2020 Oct;53(10):e12895. doi: 10.1111/cpr.12895. Epub 2020 Sep 10. PMID: 32914523; PMCID: PMC7574881. 5: Hubackova S, Davidova E, Boukalova S, Kovarova J, Bajzikova M, Coelho A, Terp MG, Ditzel HJ, Rohlena J, Neuzil J. Replication and ribosomal stress induced by targeting pyrimidine synthesis and cellular checkpoints suppress p53-deficient tumors. Cell Death Dis. 2020 Feb 7;11(2):110. doi: 10.1038/s41419-020-2224-7. PMID: 32034120; PMCID: PMC7007433. 6: de Jong Y, Bennani F, van Oosterwijk JG, Alberti G, Baranski Z, Wijers-Koster P, Venneker S, Briaire-de Bruij IH, van de Akker BE, Baelde H, Cleton-Jansen AM, van de Water B, Danen EHJ, Bovée JVMG. A screening-based approach identifies cell cycle regulators AURKA, CHK1 and PLK1 as targetable regulators of chondrosarcoma cell survival. J Bone Oncol. 2019 Nov 17;19:100268. doi: 10.1016/j.jbo.2019.100268. PMID: 31832331; PMCID: PMC6889735. 7: van Harten AM, Buijze M, van der Mast R, Rooimans MA, Martens-de Kemp SR, Bachas C, Brink A, Stigter-van Walsum M, Wolthuis RMF, Brakenhoff RH. Targeting the cell cycle in head and neck cancer by Chk1 inhibition: a novel concept of bimodal cell death. Oncogenesis. 2019 Jun 17;8(7):38. doi: 10.1038/s41389-019-0147-x. PMID: 31209198; PMCID: PMC6572811. 8: Dinkelborg PH, Wang M, Gheorghiu L, Gurski JM, Hong TS, Benes CH, Juric D, Jimenez RB, Borgmann K, Willers H. A common Chk1-dependent phenotype of DNA double-strand break suppression in two distinct radioresistant cancer types. Breast Cancer Res Treat. 2019 Apr;174(3):605-613. doi: 10.1007/s10549-018-05079-7. Epub 2019 Jan 3. PMID: 30607635; PMCID: PMC6440812. 9: Liang M, Zhao T, Ma L, Guo Y. CHK1 inhibition sensitizes pancreatic cancer cells to gemcitabine via promoting CDK-dependent DNA damage and ribonucleotide reductase downregulation. Oncol Rep. 2018 Mar;39(3):1322-1330. doi: 10.3892/or.2017.6168. Epub 2017 Dec 20. PMID: 29286153. 10: Alcaraz-Sanabria A, Nieto-Jiménez C, Corrales-Sánchez V, Serrano-Oviedo L, Andrés-Pretel F, Montero JC, Burgos M, Llopis J, Galán-Moya EM, Pandiella A, Ocaña A. Synthetic Lethality Interaction Between Aurora Kinases and CHEK1 Inhibitors in Ovarian Cancer. Mol Cancer Ther. 2017 Nov;16(11):2552-2562. doi: 10.1158/1535-7163.MCT-17-0223. Epub 2017 Aug 28. PMID: 28847989. 11: Wehler T, Thomas M, Schumann C, Bosch-Barrera J, Viñolas Segarra N, Dickgreber NJ, Dalhoff K, Sebastian M, Corral Jaime J, Alonso M, Hynes SM, Lin J, Hurt K, Bence Lin A, Calvo E, Paz-Ares L. A randomized, phase 2 evaluation of the CHK1 inhibitor, LY2603618, administered in combination with pemetrexed and cisplatin in patients with advanced nonsquamous non-small cell lung cancer. Lung Cancer. 2017 Jun;108:212-216. doi: 10.1016/j.lungcan.2017.03.001. Epub 2017 Mar 6. PMID: 28625637. 12: Laquente B, Lopez-Martin J, Richards D, Illerhaus G, Chang DZ, Kim G, Stella P, Richel D, Szcylik C, Cascinu S, Frassineti GL, Ciuleanu T, Hurt K, Hynes S, Lin J, Lin AB, Von Hoff D, Calvo E. A phase II study to evaluate LY2603618 in combination with gemcitabine in pancreatic cancer patients. BMC Cancer. 2017 Feb 15;17(1):137. doi: 10.1186/s12885-017-3131-x. PMID: 28202004; PMCID: PMC5312529. 13: Hauge S, Naucke C, Hasvold G, Joel M, Rødland GE, Juzenas P, Stokke T, Syljuåsen RG. Combined inhibition of Wee1 and Chk1 gives synergistic DNA damage in S-phase due to distinct regulation of CDK activity and CDC45 loading. Oncotarget. 2017 Feb 14;8(7):10966-10979. doi: 10.18632/oncotarget.14089. PMID: 28030798; PMCID: PMC5355238. 14: Busch CJ, Kröger MS, Jensen J, Kriegs M, Gatzemeier F, Petersen C, Münscher A, Rothkamm K, Rieckmann T. G2-checkpoint targeting and radiosensitization of HPV/p16-positive HNSCC cells through the inhibition of Chk1 and Wee1. Radiother Oncol. 2017 Feb;122(2):260-266. doi: 10.1016/j.radonc.2016.11.017. Epub 2016 Dec 9. PMID: 27939202. 15: Wayne J, Brooks T, Massey AJ. Inhibition of Chk1 with the small molecule inhibitor V158411 induces DNA damage and cell death in an unperturbed S-phase. Oncotarget. 2016 Dec 20;7(51):85033-85048. doi: 10.18632/oncotarget.13119. PMID: 27829224; PMCID: PMC5356717. 16: Calvo E, Braiteh F, Von Hoff D, McWilliams R, Becerra C, Galsky MD, Jameson G, Lin J, McKane S, Wickremsinhe ER, Hynes SM, Bence Lin A, Hurt K, Richards D. Phase I Study of CHK1 Inhibitor LY2603618 in Combination with Gemcitabine in Patients with Solid Tumors. Oncology. 2016;91(5):251-260. doi: 10.1159/000448621. Epub 2016 Sep 7. PMID: 27598338. 17: Scagliotti G, Kang JH, Smith D, Rosenberg R, Park K, Kim SW, Su WC, Boyd TE, Richards DA, Novello S, Hynes SM, Myrand SP, Lin J, Smyth EN, Wijayawardana S, Lin AB, Pinder-Schenck M. Phase II evaluation of LY2603618, a first-generation CHK1 inhibitor, in combination with pemetrexed in patients with advanced or metastatic non-small cell lung cancer. Invest New Drugs. 2016 Oct;34(5):625-35. doi: 10.1007/s10637-016-0368-1. Epub 2016 Jun 27. PMID: 27350064. 18: Signore M, Buccarelli M, Pilozzi E, De Luca G, Cappellari M, Fanciulli M, Goeman F, Melucci E, Biffoni M, Ricci-Vitiani L. UCN-01 enhances cytotoxicity of irinotecan in colorectal cancer stem-like cells by impairing DNA damage response. Oncotarget. 2016 Jul 12;7(28):44113-44128. doi: 10.18632/oncotarget.9859. PMID: 27286453; PMCID: PMC5190083. 19: Zhang Y, Lai J, Du Z, Gao J, Yang S, Gorityala S, Xiong X, Deng O, Ma Z, Yan C, Susana G, Xu Y, Zhang J. Targeting radioresistant breast cancer cells by single agent CHK1 inhibitor via enhancing replication stress. Oncotarget. 2016 Jun 7;7(23):34688-702. doi: 10.18632/oncotarget.9156. PMID: 27167194; PMCID: PMC5085184. 20: Zhao J, Niu X, Li X, Edwards H, Wang G, Wang Y, Taub JW, Lin H, Ge Y. Inhibition of CHK1 enhances cell death induced by the Bcl-2-selective inhibitor ABT-199 in acute myeloid leukemia cells. Oncotarget. 2016 Jun 7;7(23):34785-99. doi: 10.18632/oncotarget.9185. PMID: 27166183; PMCID: PMC5085189.