The ubiquitin specific protease 28 (USP28) is implicated in tumorigenesis by controlling the turnover of the oncogene c-MYC and the ubiquitin ligase FBW7. Here, we describe small molecule inhibitors of USP25 and USP28, leading to cancer cell cycle arrest and death. However, genetic deletion of USP25/28 does not replicate this effect. An integrated omics approach revealed off-target effects for thienopyridine carboxamide compounds upon the translation apparatus. Chemoproteomics and CRISPR-GOF analyses suggested binding of the compound to a region near the ribosome complex polypeptide exit tunnel. Structural analysis of a USP28-inhibitor complex enabled the design of modified USP25/28 inhibitor molecules which minimized translation-related off-target effects. In distinction to earlier compounds, the optimized inhibitors were non-toxic to breast cancer cells yet retained potent anti-proliferative activity in squamous lung carcinoma cells, where USP28 is associated with disease progression. Together, our results demonstrate that refined USP25/28 inhibitors can selectively suppress tumor growth by targeting the TP63/FBW7/c-MYC signaling axis, offering a more precise therapeutic strategy for treating squamous lung cancers whilst minimizing undesired cytotoxicity.