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A prospective compound screening contest identified broader inhibitors for Sirtuin 1.

ABSTRACT: Potential inhibitors of a target biomolecule, NAD-dependent deacetylase Sirtuin 1, were identified by a contest-based approach, in which participants were asked to propose a prioritized list of 400 compounds from a designated compound library containing 2.5 million compounds using in silico methods and scoring. Our aim was to identify target enzyme inhibitors and to benchmark computer-aided drug discovery methods under the same experimental conditions. Collecting compound lists derived from various methods is advantageous for aggregating compounds with structurally diversified properties compared with the use of a single method. The inhibitory action on Sirtuin 1 of approximately half of the proposed compounds was experimentally accessed. Ultimately, seven structurally diverse compounds were identified.

SUBMITTER: Chiba S

PROVIDER: S-EPMC6925144 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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A prospective compound screening contest identified broader inhibitors for Sirtuin 1.

Chiba Shuntaro S Ohue Masahito M Gryniukova Anastasiia A Borysko Petro P Zozulya Sergey S Yasuo Nobuaki N Yoshino Ryunosuke R Ikeda Kazuyoshi K Shin Woong-Hee WH Kihara Daisuke D Iwadate Mitsuo M Umeyama Hideaki H Ichikawa Takaaki T Teramoto Reiji R Hsin Kun-Yi KY Gupta Vipul V Kitano Hiroaki H Sakamoto Mika M Higuchi Akiko A Miura Nobuaki N Yura Kei K Mochizuki Masahiro M Ramakrishnan Chandrasekaran C Thangakani A Mary AM Velmurugan D D Gromiha M Michael MM Nakane Itsuo I Uchida Nanako N Hakariya Hayase H Tan Modong M Nakamura Hironori K HK Suzuki Shogo D SD Ito Tomoki T Kawatani Masahiro M Kudoh Kentaroh K Takashina Sakurako S Yamamoto Kazuki Z KZ Moriwaki Yoshitaka Y Oda Keita K Kobayashi Daisuke D Okuno Tatsuya T Minami Shintaro S Chikenji George G Prathipati Philip P Nagao Chioko C Mohsen Attayeb A Ito Mari M Mizuguchi Kenji K Honma Teruki T Ishida Takashi T Hirokawa Takatsugu T Akiyama Yutaka Y Sekijima Masakazu M

Scientific reports 20191220 1

Potential inhibitors of a target biomolecule, NAD-dependent deacetylase Sirtuin 1, were identified by a contest-based approach, in which participants were asked to propose a prioritized list of 400 compounds from a designated compound library containing 2.5 million compounds using in silico methods and scoring. Our aim was to identify target enzyme inhibitors and to benchmark computer-aided drug discovery methods under the same experimental conditions. Collecting compound lists derived from vari ...[more]

PMID: 31863054

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Project description:Chordoma is a rare malignant bone tumour with a poor prognosis and limited therapeutic options. We undertook a focused compound screen (FCS) against 1097 compounds on three well-characterized chordoma cell lines; 154 compounds were selected from the single concentration screen (1 µm), based on their growth-inhibitory effect. Their half-maximal effective concentration (EC50 ) values were determined in chordoma cells and normal fibroblasts. Twenty-seven of these compounds displayed chordoma selective cell kill and 21/27 (78%) were found to be EGFR/ERBB family inhibitors. EGFR inhibitors in clinical development were then studied on an extended cell line panel of seven chordoma cell lines, four of which were sensitive to EGFR inhibition. Sapitinib (AstraZeneca) emerged as the lead compound, followed by gefitinib (AstraZeneca) and erlotinib (Roche/Genentech). The compounds were shown to induce apoptosis in the sensitive cell lines and suppressed phospho-EGFR and its downstream pathways in a dose-dependent manner. Analysis of substituent patterns suggested that EGFR-inhibitors with small aniline substituents in the 4-position of the quinazoline ring were more effective than inhibitors with large substituents in that position. Sapitinib showed significantly reduced tumour growth in two xenograft mouse models (U-CH1 xenograft and a patient-derived xenograft, SF8894). One of the resistant cell lines (U-CH2) was shown to express high levels of phospho-MET, a known bypass signalling pathway to EGFR. Neither amplifications (EGFR, ERBB2, MET) nor mutations in EGFR, ERBB2, ERBB4, PIK3CA, BRAF, NRAS, KRAS, PTEN, MET or other cancer gene hotspots were detected in the cell lines. Our findings are consistent with the reported (p-)EGFR expression in the majority of clinical samples, and provide evidence for exploring the efficacy of EGFR inhibitors in the treatment of patients with chordoma and studying possible resistance mechanisms to these compounds in vitro and in vivo. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Dataset Information

A prospective compound screening contest identified broader inhibitors for Sirtuin 1.

Publications

A prospective compound screening contest identified broader inhibitors for Sirtuin 1.

Similar Datasets

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