Targeted protein degradation’s key advantage over traditional inhibitors is that it allows for drugging proteins without traditional druggable pockets. This expands therapeutic possibilities and could overcome inhibitor resistance and improve selectivity. This has been a boom in drug development and Bristol Myers Squibb is one of the leading companies that has tapped into this space. Currently, BMS has three FDA approved molecules, the most famous one is Lenalidomide.
Josh Baughman, Scientific Director and Bristol Myers Squibb discussed the development of BMS 986463: a WEE1 inhibitory kinase. BMS 986463 functions by phosphorylating CDK1 and CDK2 which slows the cell cycle to allow DNA repair. Cancer cells rely heavily on WEE1 because it shares several hallmarks of cancer such as replication stress, genomic stability and repairs damage before undergoing mitosis.
So, the WEE1 inhibitory kinase mechanism of action inhibits WEE1 by removing the brakes from the cell cycle, causing cells to enter mitosis prematurely and die due to DNA damage. There are several WEE1 kinase inhibitors are in clinical trials, with notable efficacy in ovarian and uterine serous cancers.
Moving onto in vitro studies, BMS 986463 demonstrated potent WEE1 degradation, downregulation of phospho-CDK1, induction of DNA damage, and apoptosis. Furthermore, mutation of the critical glycine in WEE1 abolished the compound’s effects, confirming on-target activity.
Alongside the positive performance in the in vitro studies, BMS 986463 showed robust tumour volume reductions in sensitive gastric and lung cancer models. The compound was particularly effective in high-grade serous ovarian cancer cell lines, aligning with clinical efficacy seen with WEE1 inhibitors. Additionally, in patient-derived xenograft (PDX) models, the compound achieved near-complete tumour regression and high levels of WEE1 degradation.
Despite the progress, Baughman noted that his team encountered and had to overcome species-specific pharmacokinetic challenges. He noticed higher clearance in mice and improved results in rats and monkeys which influenced their selection of toxicology species.
The compound is currently in clinical trials, with promising preclinical data supporting its advancement. In a nutshell BMS 986463 shows promise for indications with high replication stress and genomic instability.
