Development and structure-activity relationship study of SHP2 inhibitor containing 3,4,6-trihydroxy-5-oxo-5H-benzo[7]annulene

Bohee Kim; Seungjin Jo; Sung Bum Park; Chong Hak Chae; Kwangho Lee; Byumseok Koh; Inji Shin

doi:10.1016/j.bmcl.2019.126756

Development and structure-activity relationship study of SHP2 inhibitor containing 3,4,6-trihydroxy-5-oxo-5H-benzo[7]annulene

Bioorg Med Chem Lett. 2020 Jan 1;30(1):126756. doi: 10.1016/j.bmcl.2019.126756. Epub 2019 Nov 11.

Authors

Bohee Kim¹, Seungjin Jo², Sung Bum Park³, Chong Hak Chae³, Kwangho Lee², Byumseok Koh⁴, Inji Shin⁵

Affiliations

¹ Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea; Department of Chemistry, Chungnam University, Daejeon 28644, South Korea.
² Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea; Medicinal Chemistry & Pharmacology, Korea University of Science & Technology, Daejeon 34113, South Korea.
³ Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea.
⁴ Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea. Electronic address: bkoh@krict.re.kr.
⁵ Department of Fine Chemistry, Seoul National University of Science and Technology, Seoul 01811, South Korea; Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea; Medicinal Chemistry & Pharmacology, Korea University of Science & Technology, Daejeon 34113, South Korea. Electronic address: inji@seoultech.ac.kr.

PMID: 31784318
DOI: 10.1016/j.bmcl.2019.126756

Abstract

SHP2, a non-receptor protein tyrosine phosphatase encoded by PTPN11 gene, plays an important role in the cell growth and proliferation. Activating mutations of SHP2 have been reported as a cause of various human diseases such as solid tumors, leukemia, and Noonan syndrome. The discovery of SHP2 inhibitor can be a potent candidate for the treatment of cancers and SHP2 related human diseases. Several reports on a small molecule targeting SHP2 have published, however, there are limitations on the discovery of SHP2 phosphatase inhibitors due to the polar catalytic site environment. Allosteric inhibitor can be an alternative to catalytic site inhibitors. 3,4,6-Trihydroxy-5-oxo-5H-benzo[7]annulene 1 was obtained as an initial hit with a 0.097 μM of IC₅₀ from high-throughput screening (HTS) study. After the structure-activity relationship (SAR) study, compound 1 still showed the most potent activity against SHP2. Moreover, compound 1 exerted good potency against SHP2 expressing 2D and 3D MDA-MB-468.

Keywords: Inhibitor; PNPN11; Protein tyrosine phosphatase; SAR; SHP2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Humans
Protein Tyrosine Phosphatase, Non-Receptor Type 11 / antagonists & inhibitors*
Structure-Activity Relationship

Substances

Protein Tyrosine Phosphatase, Non-Receptor Type 11