2. Academic Validation
  3. Nanoscale Direct-to-Biology Optimization of Cdk2 Inhibitors

Nanoscale Direct-to-Biology Optimization of Cdk2 Inhibitors

  • J Med Chem. 2026 Apr 23;69(8):9142-9162. doi: 10.1021/acs.jmedchem.5c03614.
James L Douthwaite 1,  Damian J Houde 2,  Eneida Pardo 2,  Mark Moran 2,  Jason Baird 2,  Sophia R Meyer 1,  Babak Mahjour 1,  Qiyuan Zhao 1,  Jay F Larrow 2,  Yu-Pu Juang 1,  Michael J Holliday 2,  Calvin Han 2,  Brian Kelley 2,  David Dunstan 2,  Katelyn Billings 2,  Mary M Mader 2,  Alexander M Taylor 2,  Jonathan Z Sexton 1 3,  Alessandro A Boezio 2,  Tim Cernak 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 2 Relay Therapeutics, 60 Hampshire Street, Cambridge, Massachusetts 02139, United States.
  • 3 Department of Internal Medicine, Gastroenterology and Hepatology, Michigan Medicine at the University of Michigan, Ann Arbor, Michigan 48109, United States.
PMID: 41954971 DOI: 10.1021/acs.jmedchem.5c03614
Abstract

Modern hit-to-lead optimization winnows down vast chemical spaces of virtual compounds into a selection of potent and selective compounds that can be further profiled with in vitro assays. Today, miniaturized chemical synthesis can be performed in high-throughput, shifting the bottleneck to compound purification. Direct-to-biology (D2B) approaches seek to overcome this hurdle by omitting the purification step and submitting reaction mixtures directly to bioassays. Here, we explore nanoscale hit-to-lead optimization through the multistep synthesis of a library of CDK2/CycE inhibitors, utilizing ultrahigh-throughput experimentation (ultraHTE) in 1,536-well plates. Library performance is assessed by D2B in functional biochemical, bioaffinity, and X-ray crystallographic assays. A selection of potent lead CDK2/CycE inhibitors identified by D2B was submitted to a phenotypic cell painting assay, which showed cell cycle arrest at G0, consistent with CDK2 inhibition. This miniaturized workflow allows the upper tiers of a typical optimization screening cascade to be performed in a single experiment.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-183146
    Cdk2/CycE抑制剂
    CDK
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