Synthesis and Biological Activity of a VHL-Based PROTAC Specific for p38α

Abstract

We report a series of small molecule proteolysis-targeting chimeras (PROTACs) that target the protein kinase p38α for degradation. These PROTACs are based on a ligand of the VHL E3 ubiquitin ligase, which is linked to an ATP competitive inhibitor of p38α. We provide evidence that these compounds can induce the specific degradation of p38α, but not p38β and other related kinases, at nanomolar concentrations in several mammalian cell lines. We also show that the p38α-specific PROTACs are soluble in aqueous solutions and therefore suitable for their administration to mice. Systemic administration of the PROTACs induces p38α degradation only in the liver, probably due to the PROTAC becoming inactivated in that organ, but upon local administration the PROTACs induce p38α degradation in mammary tumors. Our compounds provide an alternative to traditional chemical inhibitors for targeting p38α signaling in cultured cells and in vivo.

Expanding the Structural Diversity at the Phenylene Core of Ligands for the von Hippel–Lindau E3 Ubiquitin Ligase: Development of Highly Potent Hypoxia-Inducible Factor-1α Stabilizers

“…Based on the SAR of the first-series VHL ligands, we tried to further optimize them with regard to binding affinity by introducing two additional points of diversity. An ( S )-methyl group at the benzylic position was added, as respective VHL-based PROTACs have previously shown improved VHL binding affinity and as a result also better target protein degradation potency. − ,, Furthermore, at the LHS terminus, besides the cyano group, an α-fluoro substituent at the cyclopropyl moiety has been employed for PROTAC technology, ,, and the cyano-to-fluoro replacement caused a moderate improvement in binding affinity to VHL . Both structural modifications were considered for our second series of VHL ligands, and compounds 2 and 8 were used as starting points for the following structural diversification.…”

Expanding the Structural Diversity at the Phenylene Core of Ligands for the von Hippel-Lindau (VHL) E3 Ubiquitin Ligase: Development of Highly Potent Hypoxia-Inducible Factor-1alpha (HIF-1alpha) Stabilizers

“…An (S)-methyl group at the benzylic position was added, as respective VHL-based PROTACs have previously shown improved VHL binding affinity and as a result also better target protein degradation potency. [24][25][26]41,42 Furthermore, at the LHS terminus, besides the cyano group, an α-fluoro substituent at the cyclopropyl moiety has been employed for PROTAC technology, 41,43,44 and the cyano-to-fluoro replacement caused a moderate improvement in binding affinity to VHL. 20 Both structural modifications were considered for our second series of VHL ligands and compounds 2 and 8 were used as starting points for the following structural diversification.…”

Exploring Degradation of Intrinsically Disordered Protein YAP induced by PROTACs

“…Since the design of PROTAC YAP degraders also requires a small-molecule ligand for an E3-ligase, the von Hippel-Lindau protein 1 (VHL-1)/cullin 2 E3 ligase system has been employed for the design of PROTAC degraders of a number of proteins. [39][40][41][42] We thus investigated whether the VHL-1/cullin 2 E3 ligase system can be employed here for the successful design of PROTAC YAP degraders. We used VHL ligand 2 which has been successfully used for the design of BCL-X L PROTAC degrader DT2216, which is the only VHL-recruiting PROTAC in clinical trial.…”