Drug discovery and structural analysis of the SS18-SSX reciprocal translocation fusion gene translation product that causes synovial sarcoma.

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K21470
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 47:Pharmaceutical sciences and related fields
• Research Institution: University of Tsukuba
• Principal Investigator: Iwasaki Kenji 筑波大学, 生存ダイナミクス研究センター, 教授 (20342751)
• Co-Investigator(Kenkyū-buntansha): 竹中 聡 地方独立行政法人大阪府立病院機構大阪国際がんセンター(研究所), その他部局等, 整形外科部長 (00588379)
• Project Period (FY): 2020-07-30 – 2023-03-31
• Keywords: 滑膜肉腫 / クライオ電子顕微鏡 / SBDD / 天然変性タンパク質

Outline of Final Research Achievements

The results were much greater than expected in the research plan. Expression and purification protocols were successfully established for full-length SS18-SSX1 and various fragments of SSX1 and 2. Since the majority of the proteins were found to be intrinsically disordered protein by CD measurements and other methods, we used cryo-EM single-particle analysis, solution NMR, and high-speed AFM for structural analysis instead of X-ray crystallography, and also made full use of other biochemical experiments, such as EMSA. As a result, we succeeded in elucidating its structure as a complex between the C-terminal region of SSX1 and nucleosomes (in preparation for submission for scientific publication). Furthermore, with the support of the AMED project, we were able to conduct in silico compound screening and complete this project.

Free Research Field

構造生物化学

Academic Significance and Societal Importance of the Research Achievements

滑膜肉腫はいわゆる希少がんである。がんといえば、上皮細胞由来の癌腫、造血器悪性腫瘍が取り上げられることが多く、日本における悪性腫瘍全体の1％ともいわれる肉腫の研究を念頭においた文章をみかけることは少ない。このような疾患こそアカデミアで行うべきである。今回、希少がんというだけでなく、天然変性タンパク質というSBDDとしてのアプローチの難しい原因タンパク質に対して、その端緒につくことに成功したことは非常に大きい。萌芽としての意義を100％果たし、この薬開発の可能性を見いだせた成果は大きい