2. Academic Validation
  3. Discovery and SAR Study of Boronic Acid-Based Selective PDE3B Inhibitors from a Novel DNA-Encoded Library

Discovery and SAR Study of Boronic Acid-Based Selective PDE3B Inhibitors from a Novel DNA-Encoded Library

  • J Med Chem. 2024 Feb 8;67(3):2049-2065. doi: 10.1021/acs.jmedchem.3c01562.
Ann M Rowley 1,  Gang Yao 2,  Logan Andrews 3,  Aaron Bedermann 1,  Ross Biddulph 4,  Ryan Bingham 4,  Jennifer J Brady 3,  Rachel Buxton 4,  Ted Cecconie 1,  Rona Cooper 1,  Adam Csakai 2,  Enoch N Gao 1,  Melissa C Grenier-Davies 2,  Meghan Lawler 2,  Yiqian Lian 1,  Justyna Macina 4,  Colin Macphee 4,  Lisa Marcaurelle 2,  John Martin 1,  Patricia McCormick 1,  Rekha Pindoria 4,  Martin Rauch 1,  Warren Rocque 1,  Yingnian Shen 1,  Lisa M Shewchuk 1,  Michael Squire 1,  Will Stebbeds 4,  Westley Tear 2,  Xin Wang 3,  Paris Ward 1,  Shouhua Xiao 3
Affiliations

Affiliations

  • 1 GSK, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  • 2 GSK, Encoded Library Technologies, NCE Molecular Discovery, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States.
  • 3 23andMe Inc, Therapeutics, 349 Oyster Point Boulevard, South San Francisco, California 94080, United States.
  • 4 GSK Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, Hertfordshire, U.K.
PMID: 38284310 DOI: 10.1021/acs.jmedchem.3c01562
Abstract

Human genetic evidence shows that PDE3B is associated with metabolic and dyslipidemia phenotypes. A number of PDE3 family selective inhibitors have been approved by the FDA for various indications; however, given the undesirable proarrhythmic effects in the heart, selectivity for PDE3B inhibition over closely related family members (such as PDE3A; 48% identity) is a critical consideration for development of PDE3B therapeutics. Selectivity for PDE3B over PDE3A may be achieved in a variety of ways, including properties intrinsic to the compound or tissue-selective targeting. The high (>95%) active site homology between PDE3A and B represents a massive obstacle for obtaining selectivity at the active site; however, utilization of libraries with high molecular diversity in high throughput screens may uncover selective chemical matter. Herein, we employed a DNA-encoded library screen to identify PDE3B-selective inhibitors and identified potent and selective boronic acid compounds bound at the active site.

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