Year: 2024
Type: article
Abstract: Following a phenotypic screen and predictive chemogenomics analysis, DNMDP was identified as a potent, selective PDE3 inhibitor with lung cancer cell killing activity.Proteomic analysis revealed that DNMDP treatment induces binding of PDE3A to SLFN12.In this issue, Lewis et al. (DOI: 10.1021/ acsmedchemlett.4c00336)identified a novel class of PDE3A and SLFN12 binders coined "velcrins".The binding of DNMDP to PDE3A induces an adhesive surface for SLFN12 binding, which stimulates SLFN12 ribonuclease activity�a requirement for cell death.Optimization of DNMDP resulted in BRD9500, which was active in a melanoma xenograft model.However, its short half-life and potent PDE3 inhibition resulted in potential cardiotoxicity that precluded its advancement.As a result, the goal pivoted to improving its PK properties and PDE3A selectivity.An expansive SAR campaign resulted in BAY2666605 that had low clearance and improved PDE3A selectivity and was active across a panel of cancer cell lines that overexpress PDE3A and SLFN12.Oral dosing of BAY2666605 significantly inhibited tumor growth and was efficacious in a panel of patient-derived xenografts, with tumor regression in 5 of 6 models.The team delivered a compound that was well tolerated, with no observable effects from PDE3 inhibition, and has entered Phase 1 clinical studies for metastatic melanoma and other solid cancers.
Source: ACS Medicinal Chemistry Letters
Author: Simone V. Bigi-Botterill
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4403301679