| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Outline of Final Research Achievements |
We performed optimizations of S-Trityl-L-cysteine derivatives using docking modeling, which led to the discovery of novel derivatives with fused phenyl rings in the trityl group giving low nanomolar range KSP ATPase inhibition. The representative derivatives potently inhibited cell growth in correlation with KSP inhibitory activities and significantly suppressed tumor growth in the xenograft model. We also performed SARs focused on the amino acid to enhance the drug-like properties. As a result, the introduction of various polar groups to the carboxyl group on STLC was tolerable. Additionally, we tried to synthesize new chemotype, where the sulfur atom is replaced with carbon atom. Although the final compound is not still obtained, the hydantoin intermediate showed potent inhibitory activity. Thus, the novel cysteine related derivatives could be new lead compounds in the design of clinical candidates for next-generation KSP inhibitors as antitumor chemotherapies.
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