Litronesib - CAS 910634-41-2
Catalog number:
910634-41-2
Category:
Inhibitor
Not Intended for Therapeutic Use. For research use only.
COA:
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Targets:
Ksp
Description:
litronesib, also known as LY2523355, is an inhibitor of the kinesin-related motor protein Eg5 with potential antineoplastic activity. Litronesib selectively inhibits the activity of Eg5, which may result in mitotic disruption, apoptosis and consequently cell death in tumor cells that are actively dividing. The ATP-dependent Eg5 kinesin-related motor protein (also known as KIF11 or kinesin spindle protein-5) is a plus-end directed kinesin motor protein that plays an essential role during mitosis, particularly in the regulation of spindle dynamics, including assembly and maintenance.
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Synonyms:
litronesib; LY2523355; KF 89617.
MSDS:
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Current Developer:
Eli Lilly.
1.A phase 1 and dose-finding study of LY2523355 (litronesib), an Eg5 inhibitor, in Japanese patients with advanced solid tumors.
Wakui H1, Yamamoto N, Kitazono S, Mizugaki H, Nakamichi S, Fujiwara Y, Nokihara H, Yamada Y, Suzuki K, Kanda H, Akinaga S, Tamura T. Cancer Chemother Pharmacol. 2014 Jul;74(1):15-23. doi: 10.1007/s00280-014-2467-z. Epub 2014 Apr 22.
PURPOSE: Eg5, a mitotic motor kinesin protein, plays an essential role in bipolar spindle formation in the M phase of the cell cycle. LY2523355 (litronesib) is an allosteric inhibitor of Eg5. This phase 1 and dose-finding study aimed to assess the safety, pharmacokinetics (PK), recommended dose for further studies, and preliminary efficacy in Japanese patients with advanced solid tumors.
2.Discontinued in 2013: oncology drugs.
Williams R1. Expert Opin Investig Drugs. 2015 Jan;24(1):95-110. Epub 2014 Oct 14.
Introduction: Attrition in clinical development is widely recognised as a key factor negatively impacting overall R&D efficiency. Gaining an understanding of the reasons for candidate failure may lead to improvements in success rates and return on R&D investment. Areas covered: This report provides an analysis of reasons for discontinuation of development of 40 drugs dropped from the global oncology pipeline in 2013 - the largest number of terminations reported since this annual analysis began in 2005. The article also provides discussion on the observations in the context of contemporary views of anticancer drug development. Expert opinion: Twelve drugs (30% of the 2013 discontinuations) failed in Phase III development. None of the pivotal trials investigating these agents incorporated molecular biomarkers for patient stratification. The largest number of drug terminations (20 out of 40) occurred in Phase I development with reasons for termination commonly reported as strategic or undisclosed.
3.Investigation of the mechanism of racemization of litronesib in aqueous solution: unexpected base-catalyzed inversion of a fully substituted carbon chiral center.
Baertschi SW1, Jansen PJ, Montgomery RM, Smith WK, Draper JR, Myers DP, Houghton PG, Sharp VS, Guisbert AL, Zhuang H, Watkins MA, Stephenson GA, Harris TM. J Pharm Sci. 2014 Sep;103(9):2797-808. doi: 10.1002/jps.23918. Epub 2014 Mar 14.
Mitosis inhibitor (R)-litronesib (LY2523355) is a 1,3,4-thiadiazoline-bearing phenyl and N-(2-ethylamino)ethanesulfonamido-methyl substituents on tetrahedral C5. Chiral instability has been observed at pH 6 and above with the rate of racemization increasing with pH. A positively charged trigonal intermediate is inferred from the fact that p-methoxy substituent on the phenyl accelerated racemization, whereas a p-trifluoromethyl substituent had the opposite effect. Racemization is proposed to occur through a relay mechanism involving intramolecular deprotonation of the sulfonamide by the side chain amino group and attack of the sulfonamide anion on C5, cleaving the C5S bond, to form an aziridine; heterolytic dissociation of the aziridine yields an ylide. This pathway is supported by (1) a crystal structure providing evidence for a hydrogen bond between the sulfonamide NH and the amino group, (2) effects of substituents on the rate of racemization, and (3) computational studies.
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