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Integrated phenotypic screening and activity-based protein profiling to reveal potential therapy targets of

Wenyan Liu1, Zhang Zhang, Zhi-Min Zhang

  • 1School of Pharmacy, Jinan University; Guangzhou City Key Laboratory of Precision Chemical Drug Development; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MOE) of People's Republic of China, 601 Huangpu Avenue West, Guangzhou, 510632, China. pharmlzq@jnu.edu.cn.

Chemical Communications (Cambridge, England)
|January 19, 2019
PubMed

Insights

Researchers identified novel therapeutic targets for pancreatic cancer by screening a compound library. Two potent inhibitors, P21 and P26, were discovered, with GSTO1 validated as a key target to impair cancer cell survival.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Proteomics

Background:

  • Pancreatic cancer presents significant treatment challenges with limited validated therapeutic targets.
  • Identifying novel strategies to combat this complex disease is crucial.

Purpose of the Study:

  • To discover and validate new therapeutic targets for pancreatic cancer.
  • To identify potent small molecules that inhibit pancreatic cancer cell survival.

Main Methods:

  • A 61-compound library was synthesized using the Ugi reaction.
  • Phenotypic screening was employed to identify active compounds.
  • Quantitative chemoproteomics was used to identify protein targets.
  • GSTO1 was validated as a key cellular target.

Main Results:

  • Two potent inhibitors, P21 and P26, were discovered, significantly reducing BxPC-3 pancreatic cancer cell survival.
  • Proteins including GSTO1, FAM213A, RAB6A/6B/39A, and USMG5 were identified as interacting partners.
  • GSTO1 was confirmed as the primary cellular target.

Conclusions:

  • GSTO1 represents a novel and validated therapeutic target for pancreatic cancer.
  • The identified inhibitors demonstrate potential for further drug development against pancreatic cancer.

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