Potent, Selective Inhibitor of an Emerging Therapeutic Target for Cancer

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2019-KRUS-68554
Researchers at Purdue University have developed a selective and potent compound against an emerging therapeutic target, chromobox (CBX) 8, a protein identified as a potential oncogenic target in lymphoma, hepatocellular carcinoma, breast cancer, and leukemia. CBX8 is a member of a family of highly homologous proteins with binding pockets that are difficult to target with traditional small molecules. For those reasons, current CBX inhibitors display weak affinity and poor selectivity. The current molecules also exhibit limited cellular permeability and toxicity to many normal cell types. The Purdue researchers used a DNA-encoded chemical library to identify a new peptidomimetic ligand for CBX8. This compound offers high affinity of around 400-800 nM, is >5-20-fold more selective for CBX8 versus other family members, and is cell permeable. The ligand's mechanism of action was confirmed in cell culture. It inhibits growth of a mixed-lineage leukemia cell line, THP1, that is known to be CBX8-dependent but does not inhibit a control leukemia cell line, K562, with a different genetic driver. This inhibitor has the potential to help researchers and pharmaceutical companies better understand CBX8's potential as a therapeutic target to prevent cancer growth and chemotherapy resistance.

Advantages:
-High affinity
-Selectivity for CBX8 over other related proteins
-Cell permeable

Potential Applications:
-Drug Development


Related Publication:
Optimization of Ligands Using Focused DNA-Encoded Libraries To Develop a Selective, Cell-Permeable CBX8 Chromodomain Inhibitor
ACS Chem. Biol. 2020, 15, 112−131
DOI: 10.1021/acschembio.9b00654
May 18, 2021
CIP-Gov. Funding
United States
(None)
(None)

Jun 5, 2020
Utility-Gov. Funding
United States
(None)
(None)

Jun 7, 2019
Provisional-Patent
United States
(None)
(None)
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