Ispinesib - CAS 336113-53-2
Catalog number: 336113-53-2
Category: Inhibitor
Not Intended for Therapeutic Use. For research use only.
Ispinesib is a synthetic small molecule, derived from quinazolinone, with antineoplastic properties. Ispinesib selectively inhibits the mitotic motor protein, kinesin spindle protein (KSP), resulting in inhibition of mitotic spindle assembly, induction of cell cycle arrest during the mitotic phase, and cell death in tumor cells that are actively dividing. Because KSP is not involved in nonmitotic processes, such as neuronal transport, ispinesib may be less likely to cause the peripheral neuropathy often associated with the tubulin-targeting agents.
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SB-715992; SB715992; SB 715992; CK 0238273; CK-0238273; CK0238273.
Current Developer:
GlaxoSmithKline and Cytokinetics
1.The structure of the ternary Eg5-ADP-ispinesib complex.
Talapatra SK1, Schüttelkopf AW, Kozielski F. Acta Crystallogr D Biol Crystallogr. 2012 Oct;68(Pt 10):1311-9. Epub 2012 Sep 13.
The human kinesin Eg5 is responsible for bipolar spindle formation during early mitosis. Inhibition of Eg5 triggers the formation of monoastral spindles, leading to mitotic arrest that eventually causes apoptosis. There is increasing evidence that Eg5 constitutes a potential drug target for the development of cancer chemotherapeutics. The most advanced Eg5-targeting agent is ispinesib, which exhibits potent antitumour activity and is currently in multiple phase II clinical trials. In this study, the crystal structure of the Eg5 motor domain in complex with ispinesib, supported by kinetic and thermodynamic binding data, is reported. Ispinesib occupies the same induced-fit pocket in Eg5 as other allosteric inhibitors, making extensive hydrophobic interactions with the protein. The data for the Eg5-ADP-ispinesib complex suffered from pseudo-merohedral twinning and revealed translational noncrystallographic symmetry, leading to challenges in data processing, space-group assignment and structure solution as well as in refinement.
2.DrugTargetSeqR: a genomics- and CRISPR-Cas9-based method to analyze drug targets.
Kasap C1, Elemento O2, Kapoor TM1. Nat Chem Biol. 2014 Aug;10(8):626-8. doi: 10.1038/nchembio.1551. Epub 2014 Jun 15.
To identify physiological targets of drugs and bioactive small molecules, we developed an approach, named DrugTargetSeqR, which combines high-throughput sequencing, computational mutation discovery and clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9-based genome editing. We applied this approach to ispinesib and YM155, drugs that have undergone clinical trials as anticancer agents, and uncovered mechanisms of action and identified genetic and epigenetic mechanisms likely to cause drug resistance in human cancer cells.
3.Optimized S-trityl-L-cysteine-based inhibitors of kinesin spindle protein with potent in vivo antitumor activity in lung cancer xenograft models.
Good JA1, Wang F, Rath O, Kaan HY, Talapatra SK, Podgórski D, MacKay SP, Kozielski F. J Med Chem. 2013 Mar 14;56(5):1878-93. doi: 10.1021/jm3014597. Epub 2013 Feb 27.
The mitotic kinesin Eg5 is critical for the assembly of the mitotic spindle and is a promising chemotherapy target. Previously, we identified S-trityl-L-cysteine as a selective inhibitor of Eg5 and developed triphenylbutanamine analogues with improved potency, favorable drug-like properties, but moderate in vivo activity. We report here their further optimization to produce extremely potent inhibitors of Eg5 (K(i)(app) < 10 nM) with broad-spectrum activity against cancer cell lines comparable to the Phase II drug candidates ispinesib and SB-743921. They have good oral bioavailability and pharmacokinetics and induced complete tumor regression in nude mice explanted with lung cancer patient xenografts. Furthermore, they display fewer liabilities with CYP-metabolizing enzymes and hERG compared with ispinesib and SB-743921, which is important given the likely application of Eg5 inhibitors in combination therapies. We present the case for this preclinical series to be investigated in single and combination chemotherapies, especially targeting hematological malignancies.
4.Functional genetic screens identify genes essential for tumor cell survival in head and neck and lung cancer.
Martens-de Kemp SR1, Nagel R, Stigter-van Walsum M, van der Meulen IH, van Beusechem VW, Braakhuis BJ, Brakenhoff RH. Clin Cancer Res. 2013 Apr 15;19(8):1994-2003. doi: 10.1158/1078-0432.CCR-12-2539. Epub 2013 Feb 26.
PURPOSE: Despite continuous improvement of treatment regimes, the mortality rates for non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC) remain disappointingly high and novel anticancer agents are urgently awaited.
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