LY2603618

• CAT Number: I005431
• CAS Number: 911222-45-2
• Molecular Formula: C18H22BrN5O3
• Molecular Weight: 436.3
• Purity: ≥95%
• Target: Chk
• Solubility: DMSO: ≤ 29.5 mg/mL
• Storage: 3 years -20C powder
• IC50: 7 nM
• InChIKey: SYYBDNPGDKKJDU-ZDUSSCGKSA-N

LY2603618(IC-83) is a potent and selective small molecule inhibitor of Chk1 protein kinase activity in vitro (IC50=7 nM) and the first selective Chk1 inhibitor to enter clinical cancer trials.


in vitro: LY2603618 treatment impairs DNA synthesis, increases DNA damage (via mitotic defects), induces apoptosis, and has synergistic activity with pemetrexed, especially in p53 mutant tumor cells. Chk1 is an ATP-dependent serine-threonine kinase and a key component in the DNA replication-monitoring checkpoint system activated by double-stranded breaks (DSBs). Chk1 contributes to all currently defined cell cycle checkpoints, including G1/S, intra-S-phase, G2/M, and the mitotic spindle checkpoint. By inhibiting the activity of chk1, LY2603618 prevents the repair of DNA caused by DNA-damaging agents, thus potentiating the antitumor efficacies of various chemotherapeutic agents. However, preclinical data involving LY2603618 has not been published until now. 


in vivo: In xenograft models, LY2603618 delays tumor growth when given in combination with pemetrexed.

Reference

1:A phase II study to evaluate LY2603618 in combination with gemcitabine in pancreatic cancer patients. 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.BMC Cancer. 2017 Feb 15;17(1):137. doi: 10.1186/s12885-017-3131-x. PMID: 28202004 Free PMC Article2:Phase I Study of CHK1 Inhibitor LY2603618 in Combination with Gemcitabine in Patients with Solid Tumors. 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.Oncology. 2016;91(5):251-260. Epub 2016 Sep 7. PMID: 27598338 3: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. 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.Invest New Drugs. 2016 Oct;34(5):625-35. doi: 10.1007/s10637-016-0368-1. Epub 2016 Jun 27. PMID: 27350064 4:LY2603618, a selective CHK1 inhibitor, enhances the anti-tumor effect of gemcitabine in xenograft tumor models. Barnard D, Diaz HB, Burke T, Donoho G, Beckmann R, Jones B, Barda D, King C, Marshall M.Invest New Drugs. 2016 Feb;34(1):49-60. doi: 10.1007/s10637-015-0310-y. Epub 2015 Nov 27. PMID: 26612134 5:Phase I study of LY2603618, a CHK1 inhibitor, in combination with gemcitabine in Japanese patients with solid tumors. Doi T, Yoshino T, Shitara K, Matsubara N, Fuse N, Naito Y, Uenaka K, Nakamura T, Hynes SM, Lin AB.Anticancer Drugs. 2015 Nov;26(10):1043-53. doi: 10.1097/CAD.0000000000000278. PMID: 26288133 6:Evaluation of the likelihood of a selective CHK1 inhibitor (LY2603618) to inhibit CYP2D6 with desipramine as a probe substrate in cancer patients. Hynes SM, Wickremsinhe E, Zhang W, Decker R, Ott J, Chandler J, Mitchell M.Biopharm Drug Dispos. 2015 Jan;36(1):49-63. doi: 10.1002/bdd.1922. Epub 2014 Nov 14. PMID: 25296725 7:Preclinical analyses and phase I evaluation of LY2603618 administered in combination with pemetrexed and cisplatin in patients with advanced cancer. Calvo E, Chen VJ, Marshall M, Ohnmacht U, Hynes SM, Kumm E, Diaz HB, Barnard D, Merzoug FF, Huber L, Kays L, Iversen P, Calles A, Voss B, Lin AB, Dickgreber N, Wehler T, Sebastian M.Invest New Drugs. 2014 Oct;32(5):955-68. doi: 10.1007/s10637-014-0114-5. Epub 2014 Jun 20. PMID: 24942404 8:The checkpoint 1 kinase inhibitor LY2603618 induces cell cycle arrest, DNA damage response and autophagy in cancer cells. Wang FZ, Fei HR, Cui YJ, Sun YK, Li ZM, Wang XY, Yang XY, Zhang JG, Sun BL.Apoptosis. 2014 Sep;19(9):1389-98. doi: 10.1007/s10495-014-1010-3. PMID: 24928205 9:Disposition and metabolism of LY2603618, a Chk-1 inhibitor following intravenous administration in patients with advanced and/or metastatic solid tumors. Wickremsinhe ER, Hynes SM, Palmieri MD, Mitchell MI, Abraham TL, Rehmel JF, Chana E, Jost LM, Cassidy KC.Xenobiotica. 2014 Sep;44(9):827-41. doi: 10.3109/00498254.2014.900589. Epub 2014 Mar 26. PMID: 24666335 10:Characterization and preclinical development of LY2603618: a selective and potent Chk1 inhibitor. King C, Diaz H, Barnard D, Barda D, Clawson D, Blosser W, Cox K, Guo S, Marshall M.Invest New Drugs. 2014 Apr;32(2):213-26. doi: 10.1007/s10637-013-0036-7. Epub 2013 Oct 10. PMID: 24114124