Development and Utility of a PAK1-Selective Degrader

Abstract

Overexpression of PAK1, a druggable kinase, is common in several malignancies, and inhibition of PAK1 by small molecules has been shown to impede the growth and survival of such cells. Potent inhibitors of PAKs 1−3 have been described, but clinical development has been hindered by recent findings that PAK2 function is required for normal cardiovascular function in adult mice. A unique allosteric PAK1-selective inhibitor, NVS-PAK1-1, provides a potential path forward, but has modest potency. Here, we report the development of BJG-05-039, a PAK1selective degrader consisting of NVS-PAK1-1 conjugated to lenalidomide, a recruiter of the E3 ubiquitin ligase substrate adaptor Cereblon. BJG-05-039 induced selective degradation of PAK1 and displayed enhanced antiproliferative effects relative to its parent compound in PAK1-dependent, but not PAK2-dependent, cell lines. Our findings suggest that selective PAK1 degradation may confer more potent pharmacological effects compared with catalytic inhibition and highlight the potential advantages of PAK1-targeted degradation.

Fragment-to-Lead Medicinal Chemistry Publications in 2022

“…52 Clinical candidates were exemplified in three of the entries (entries 6, 10, and 13), 16,19,22 and a fourth entry (entry 4) 14 mentions that clinical candidates have been identified but not disclosed. As mentioned in an earlier section, FBDD has begun to be used for PPI stabilization (14-3-3) 41 and targeted protein degradation (PAK1 degrader); 44 we expect this trend to continue. Future areas for FBDD evolution could be rapid fragment hit follow-up using poised DNA encoded libraries and the use of cryo-EM for FBDD to enable new target classes.…”

“…PPI stabilization has begun to gain momentum within the drug discovery community. Stabilizing physiological relevant PPIs or inducing new PPIs with components of the ubiquitin ligase system forms the basis of targeted protein degradation, which is exemplified by the development of a fragment-derived, selective PAK1 degrader. , It will be interesting to see how these approaches continue to evolve in the coming years.…”

Inhibition of P21-activated kinases 1 and 4 synergistically suppress the growth of pancreatic cancer by stimulating anti-tumour immunity

“…However, pan-PAK inhibitors have a high level of toxicity as PAK2 inhibition can lead to endothelial cell dysfunction and vascular malformation [33]. Recent development of a selective PAK1 degrader by proteolysis-targeting chimera (PROTAC) technique has increased the hope of developing more selective PAK inhibitors [34]. Whether the combination of selective PAK1 and PAK4 degraders can offer greater clinical e cacy while minimizing side effects remains a question to be addressed and requires further research.…”

Inhibition of P21-activated kinases 1 and 4 synergistically suppresses the growth of pancreatic cancer by stimulating anti-tumour immunity

“…However, pan-PAK inhibitors have a high level of toxicity as PAK2 inhibition can lead to endothelial cell dysfunction and vascular malformation [ 33 ]. Recent development of a selective PAK1 degrader by proteolysis-targeting chimera (PROTAC) technique has increased the hope of developing more selective PAK inhibitors [ 34 ]. Whether the combination of selective PAK1 and PAK4 degraders can offer greater clinical efficacy while minimizing side effects remains a question to be addressed and requires further research.…”