Development of novel small molecules degrading microtubule-associated proteins

2016 Fiscal Year Final Research Report

• Project/Area Number: 26860049
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Biological pharmacy
• Research Institution: National Institute of Health Sciences
• Principal Investigator: Ohoka Nobumichi 国立医薬品食品衛生研究所, 遺伝子医薬部, 室長 (80568519)
• Research Collaborator: Naito Mikihiko 国立医薬品食品衛生研究所, 遺伝子医薬部, 部長 (00198011)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: TACC3 / SNIPER / ユビキチン / プロテアソーム / がん / 細胞死

Outline of Final Research Achievements

We have developed SNIPER compounds that induce selective degradation of target proteins. In this study, we designed and synthesized SNIPER(TACC3)s, which target the spindle regulatory protein TACC3. SNIPER(TACC3)s induce ubiquitylation and proteasomal degradation of TACC3 in cells. Mechanistic analysis indicated that APC/CCDH1 mediates the SNIPER(TACC3)-induced degradation of TACC3. SNIPER(TACC3) selectively induced apoptosis in cancer cells expressing a larger amount of TACC3 than normal cells.
SNIPER(TACC3) also induced paraptosis-like cell death selectively in cancer cells. Mechanistic analysis suggests that accumulation of ubiquitylated protein aggregates that requires XIAP induces ER-stress responses involving XBP-1 and ER-derived vacuolization in cancer cells. Importantly, inhibition of proteasome enhanced SNIPER(TACC3)-induced vacuolization, and combination treatment of SNIPER(TACC3) and bortezomib exhibited a synergistic anticancer activity in several cancer cell lines.

Free Research Field

生物系薬学