Modular PROTAC Design for the Degradation of Oncogenic BCR‐ABL

Abstract

Proteolysis Targeting Chimera (PROTAC) technology is a rapidly emerging alternative therapeutic strategy with the potential to address many of the challenges currently faced in modern drug development programs. PROTAC technology employs small molecules that recruit target proteins for ubiquitination and removal by the proteasome. The synthesis of PROTAC compounds that mediate the degradation of c-ABL and BCR-ABL by recruiting either Cereblon or Von Hippel Lindau E3 ligases is reported. During the course of their development, we discovered that the capacity of a PROTAC to induce degradation involves more than just target binding: the identity of the inhibitor warhead and the recruited E3 ligase largely determine the degradation profiles of the compounds; thus, as a starting point for PROTAC development, both the target ligand and the recruited E3 ligase should be varied to rapidly generate a PROTAC with the desired degradation profile.

Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition

“…In this context, it is important that compounds do not induce a HIF-dependent response, which would otherwise confound or interfere with the desired biological effect resulting from induced target knockdown. The results of this study reveal an exploitable concentration window between the desired PROTAC activity (observed in the pM-nM range656667) and the HIF-stabilizing activity (observed in the μM range with VHL inhibitors, documented here).…”

Cereblon and its downstream substrates as molecular targets of immunomodulatory drugs

“…Surprisingly, this chemical compound was found to enhance the degradation of BRD4 via its binding to CRBN. target of chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL), they are well on their way to designing a degradation system for BCR-ABL [45]. Although there are many uncovered issues, such as offtarget protein degradation and the interference of internal ligands to therapeutic effects, the development of drugs via controlling the degradation of various proteins of interest using CRBN is currently a topic of utmost interest.…”

The chimeric ubiquitin ligase SH2-U-box inhibits the growth of imatinib-sensitive and resistant CML by targeting the native and T315I-mutant BCR-ABL

“…One of such approach is a chemical Proteolysis Targeting Chimera (PROTAC), in which a heterobifunctional molecule recruits a specific protein target to an E3 ubiquitin ligase, resulting in the target’s ubiquitination and degradation414445. This technology has been actively employed to degrade the oncoproteins, such as ERα, AR46, BRD447, as well as BCR-ABL48. Another approach is to create a non-endogenous, chimeric E3 ubiquitin ligase that can specifically target the proteins of interest, by replacing the “recognizing and binding” region of an endogenous E3 by an adaptor molecule or directly fusing an E3 “catalytic” domain with an interacting domain of a specific adaptor.…”

“…It is possible that the amount or the conformational structure of SH2-U-box is still not optimal for BCR-ABL degradation. Most recently, Lai et al 48. screened several PROTACs that were designed for the degradation of BCR-ABL/c-ABL and found only some of them works, where the degradation profiles were determined not only by the “ligand” for BCR-ABL/c-ABL, but also by the recruited E3 ligase.…”