Discovery of Potent and Selective Reversible Ubiquitin-Like Modifier Activating Enzyme 5 Inhibitors Targeting the UFMylation Pathway
Ubiquitin-like modifier activating enzyme 5 (UBA5), an E1 enzyme in the UFMylation pathway, is of interest as a therapeutic target in diseases such as cancer due to the critical role that UFMylation plays in cellular function. Strategic structure-activity relationship optimization of high-throughput screen hit <b>6</b>, a Bruton's tyrosine kinase covalent inhibitor, was conducted by using both conventional and microscale library synthesis. This approach identified <b>49</b> and <b>50</b> as potent and selective noncovalent UBA5 inhibitors with significantly improved surface plasmon resonance and nanodifferential scanning fluorimetry biophysical profiles. Cellular target engagement for <b>49</b> and <b>50</b> was confirmed by a cellular thermal shift assay and translated to inhibition of UFMylation of UBA5 and UFC1 in retinal pigment epithelial-1 cells as well as reduction of UFMylation of the downstream protein UFMylation substrate RPL26. Furthermore, <b>49</b> and <b>50</b> demonstrated specificity for UBA5 among the other E1-E2 transesterification pathways. In this communication, we report the discovery and synthesis of potent and selective UBA5 inhibitors, providing valuable tool compounds for studying the UFMylation pathway.
Authors
- Frank Marsilio (ORCID: https://orcid.org/0000-0003-3230-1142)
- Joseph Yanchunas
- Stephen T. Wrobleski (ORCID: https://orcid.org/0000-0001-7793-1530)
- R. Michael Lawrence
- David D. Weis (ORCID: https://orcid.org/0000-0003-3032-1211)
- Elizabeth A. Jurica (ORCID: https://orcid.org/0000-0003-3689-5451)
- Chunhong Yan (ORCID: https://orcid.org/0000-0002-3974-7991)
- M.K. Manik (ORCID: https://orcid.org/0000-0001-9510-2250)
- Erik C. Vik (ORCID: https://orcid.org/0000-0003-1334-0293)
- Selyna Mai
- Darby Ball (ORCID: https://orcid.org/0000-0001-6379-6294)
- Steven A. Spronk (ORCID: https://orcid.org/0000-0002-2851-2572)
- Brian P. Mahon (ORCID: https://orcid.org/0000-0002-5571-8058)
- Smriti Srivastava (ORCID: https://orcid.org/0000-0001-5678-7058)
- Jaclyn Robustelli
- Dawn Mulligan
- Bruce A. Ellsworth (ORCID: https://orcid.org/0000-0002-2788-1819)
- Andrew F. Donnell (ORCID: https://orcid.org/0000-0002-1137-3959)
- John A. Newitt (ORCID: https://orcid.org/0000-0001-7324-715X)
- James Mignone
- Cullen L. Cavallaro (ORCID: https://orcid.org/0000-0001-9498-2612)
- Jeffrey Tredup
- Deepa Rajasekaran (ORCID: https://orcid.org/0000-0002-4596-2989)
- Peter Kalev
- Courtney T. McCarthy
- Sarah C. Traeger
- Qi Guo (ORCID: https://orcid.org/0000-0001-6762-2929)
- Joanne J. Bronson (ORCID: https://orcid.org/0009-0003-9719-3493)
- Konstantinos J. Mavrakis
- Ping Zhang (ORCID: https://orcid.org/0000-0001-9163-6191)
- Ling Li (ORCID: https://orcid.org/0000-0003-3923-5184)
- Sumit Joshi (ORCID: https://orcid.org/0000-0002-3754-5157)
- Phong Quang
- Payal R. Sheth
- Paramasivam Murugan
- Emma Lees
- Farya J. Chattergoon
Institutions
- Bristol-Myers Squibb (Germany) (DE)
- Bristol-Myers Squibb (Sweden) (SE)
- Bristol-Myers Squibb (Belgium) (BE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-09-25
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c02305
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.00