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. 2015 Jul 21;6(8):919-24.
doi: 10.1021/acsmedchemlett.5b00179. eCollection 2015 Aug 13.

Discovery, SAR, and X-ray Binding Mode Study of BCATm Inhibitors from a Novel DNA-Encoded Library

Hongfeng Deng  1 , Jingye Zhou  1 , Flora S Sundersingh  1 , Jennifer Summerfield  1 , Don Somers  2 , Jeffrey A Messer  1 , Alexander L Satz  1 , Nicolas Ancellin  3 , Christopher C Arico-Muendel  1 , Katie L Sargent Bedard  1 , Arthur Beljean  2 , Svetlana L Belyanskaya  1 , Ryan Bingham  2 , Sarah E Smith  2 , Eric Boursier  3 , Paul Carter  2 , Paolo A Centrella  1 , Matthew A Clark  1 , Chun-Wa Chung  2 , Christopher P Davie  1 , Jennifer L Delorey  1 , Yun Ding  1 , G Joseph Franklin  1 , LaShadric C Grady  1 , Kenny Herry  3 , Clare Hobbs  2 , Christopher S Kollmann  1 , Barry A Morgan  1 , Laura J Pothier Kaushansky  1 , Quan Zhou  4
Affiliations

Discovery, SAR, and X-ray Binding Mode Study of BCATm Inhibitors from a Novel DNA-Encoded Library

Hongfeng Deng et al. ACS Med Chem Lett. .

Abstract

As a potential target for obesity, human BCATm was screened against more than 14 billion DNA encoded compounds of distinct scaffolds followed by off-DNA synthesis and activity confirmation. As a consequence, several series of BCATm inhibitors were discovered. One representative compound (R)-3-((1-(5-bromothiophene-2-carbonyl)pyrrolidin-3-yl)oxy)-N-methyl-2'-(methylsulfonamido)-[1,1'-biphenyl]-4-carboxamide (15e) from a novel compound library synthesized via on-DNA Suzuki-Miyaura cross-coupling showed BCATm inhibitory activity with IC50 = 2.0 μM. A protein crystal structure of 15e revealed that it binds to BCATm within the catalytic site adjacent to the PLP cofactor. The identification of this novel inhibitor series plus the establishment of a BCATm protein structure provided a good starting point for future structure-based discovery of BCATm inhibitors.

Keywords: BCATm; DNA Encoded Library; ELT; obesity; on-DNA Suzuki−Miyaura cross-coupling reaction.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Synthesis of the Three Cycle DNA Encoded CIA Library
Scheme 2
Scheme 2. Off-DNA Synthesis of Representative Compounds Selected by BCATm
Reagents and conditions: (a) diisopropyl azodicarboxylate, PPh3, tert-butyl 3-hydroxypyrrolidine-1-carboxylate; (b) (i) NaOH, THF-MeOH, H2O; (ii) HATU, DIEA, MeNH2·HCl, AcCN; (c) boronic acids, Pd(PPh3)4, Cs2CO3, THF/H2O, N2, 80 °C, 2 h; (d) (i) 10% TFA/DCM; (ii) HATU, DIEA, R2COOH, AcCN; (e) H2 balloon, 10% Pd/C, MeOH; (f) (i) 10% TFA/DCM; (ii) HATU, DIEA, 5-bromothiophene-2-carboxylic acid, AcCN.
Figure 1
Figure 1
Spotfire cube data view of BCATm selection features. BB1, cycle 1 building blocks; BB2, cycle 2 building blocks; and BB3, cycle 3 building blocks. Color of the dots represents different levels of enrichment (pink is 50-fold, blue is 20-fold, green is 10-fold, and yellow is 5-fold). To simplify the visualization, only selection features of building block 5 with copy counts ≥2 were shown in the cube.
Figure 2
Figure 2
First group of off-DNA compounds and activities against BCATm.
Figure 3
Figure 3
Structures and activities for analogues of compound 15d.
Figure 4
Figure 4
Views of X-ray crystal structure of BCATm in complex with 15e (in cyan) and cofactor PLP (in yellow).
See this image and copyright information in PMC

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