Designing HDAC-PROTACs: Lessons Learned So Far

Abstract

Proteolysis-targeting chimeras (PROTACs) are a powerful tool to hijack the endogenous ubiquitin-proteasome system (UPS) and to degrade the intracellular proteins of therapeutic importance. Recently, two heterobifunctional degraders targeting hormone receptors headed into Phase II clinical trials. Compared to traditional drug design and common modes of action, the PROTAC approach offers new opportunities for the drug research field. Histone deacetylase inhibitors (HDACi) are well-established drugs for the treatment of hematological malignancies. The integration of HDAC binding motifs in PROTACs explores the possibility of targeted, chemical HDAC degradation. This review provides an overview and a perspective about the key steps in the structure development of HDAC–PROTACs. In particular, the influence of the three canonical PROTAC elements on HDAC–PROTAC efficacy and selectivity are discussed, the HDACi, the linker and the E3 ligase ligand.

HDAC Inhibitors for the Therapy of Triple Negative Breast Cancer

“…They are bifunctional compounds showing a moiety that has the ability to bind to the E3 ubiquitin ligase, such as the cereblon (CRBN) and von Hippel-Lindau (VHL) ligands [58], and a HDAC binding group connected by a suitable linker. By forming a ternary complex E2 ligase:PROTAC:HDAC, they have the ability to trigger the ubiquitin-proteasome system (UPS), inducing the HDAC degradation [59,60]. Moreover, an interesting isoform selectivity can be achieved through the introduction of the appropriate HDAC binding moiety.…”

Targeting Histone Deacetylases: Opportunities for Cancer Treatment and Chemoprevention

“…In 2018, one of the first HDAC-targeting PROTACs was described as the first HDAC6 degrader, generated based on nonselective HDAC inhibitors with E3 ubiquitin ligase ligand pomalidomide as cereblon (CRBN) (Table 5). CRBN ligands rely on the structure of the anticancer drug thalidomide and its derivatives [247]. The PROTAC compound exhibits a degrader concentration (DC) 50 of 34 nM and a maximum percentage of HDAC6 degradation (D max ) of 70.5% without significant effects on other HDACs family members.…”

“…In addition, a cell-permeable HDAC-targeting PROTAC based on Von Hippel-Lindau (VHL) as an E3 ligase-binding motif and Nexturastat A (Next-A), a well-known HDAC6selective inhibitor, has been synthesized. VHL has demonstrated efficacy and the robust degradation of a wide range of protein targets and shown the ability to bypass the possible off-target effects of CRBN recruitment [247]. The resulting PROTAC agent induces HDAC6 degradation with a DC 50 of 7.1 nM and a D max of 90% in the MM1S cell line [251].…”

“…Finally, Cao et al used bestatin, a cellular inhibitor of apoptosis (cIAP) ligand, as E3 ligase-binding motifs to develop cIAP-HDAC-PROTACs [254]. Namely, cIAP ligands function as E3 ubiquitin ligases that target RIP1 for polyubiquitination and have shown success in the design of PROTACs [247,255]. Several HDAC-cIAP hybrid molecules were synthesized and one in particular, named P1, significantly reduced the HDAC1, HDAC6, and HDAC8 expression levels on the B lymphocytes cell line RPMI-8226 after 24 h treatment, at concentrations ranging from 1 µM to 4 µM, although it did not induce HDAC degradation at 6 h of treatment [255].…”

Development of the first non-hydroxamate selective HDAC6 degraders

“…HDAC6 is overexpressed in various cancer types and modulates the activity of several non-histone proteins such as α-tubulin, cortactin, and Hsp90. 2 Since the knockout of HDAC6 in mice did not produce significant defects, HDAC6 inhibitors are considered to exhibit improved safety profiles compared to pan-HDACi. 3 HDAC6 is structurally unique and comprises two active catalytic domains (CD1 and CD2) as well as a zinc finger functioning as an ubiquitin-binding domain (UBD).…”