Discovery of Novel Pyrazolo-pyridone DCN1 Inhibitors Controlling Cullin Neddylation

• Published in: Journal of medicinal chemistry Vol. 62; no. 18; pp. 8429 - 8442
• Main Authors: Kim, Ho Shin, Hammill, Jared T, Scott, Daniel C, Chen, Yizhe, Min, Jaeki, Rector, Jonah, Singh, Bhuvanesh, Schulman, Brenda A, Guy, R. Kiplin
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.09.2019; Amer Chemical Soc; American Chemical Society (ACS)
• Subjects: assays; BASIC BIOLOGICAL SCIENCES; cells; Chemistry, Medicinal; inhibitors; INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Life Sciences & Biomedicine; mixtures; Pharmacology & Pharmacy; Science & Technology; substituents; SQUAMOUS-CELL-CARCINOMA; SYSTEM; N-TERMINAL ACETYLATION; COMPLEX; GROWTH; SCCRO DCUN1D1; PROLIFERATION; UBIQUITIN LIGASES; CARCINOMA-RELATED ONCOGENE; FAMILY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.9b00410

Chemical control of cullin neddylation is attracting increased attention based largely on the successes of the NEDD8-activating enzyme (E1) inhibitor pevonedistat. Recently reported chemical probes enable selective and time-dependent inhibition of downstream members of the neddylation trienzymatic cascade including the co-E3, DCN1. In this work, we report the optimization of a novel class of small molecule inhibitors of the DCN1-UBE2M interaction. Rational X-ray co-structure enabled optimization afforded a 25-fold improvement in potency relative to the initial screening hit. The potency gains are largely attributed to additional hydrophobic interactions mimicking the N-terminal acetyl group that drives binding of UBE2M to DCN1. The compounds inhibit the protein–protein interaction, block NEDD8 transfer in biochemical assays, engage DCN1 in cells, and selectively reduce the steady-state neddylation of Cul1 and Cul3 in two squamous carcinoma cell lines harboring DCN1 amplification.