Structure-Based Discovery of Selective Histone Deacetylase 8 Degraders with Potent Anticancer Activity

Abstract

Inducing protein degradation by proteolysis targeting chimeras has gained tremendous momentum as a promising novel therapeutic strategy. Here, we report the design, synthesis, and biological characterization of highly potent proteolysis targeting chimeric small molecules targeting the epigenetic regulator histone deacetylase 8 (HDAC8). We developed potent and effective HDAC8 degraders, as exemplified by SZUH280 (16e), which effectively induced HDAC8 protein degradation and inhibited cancer cell growth even at low micromolar concentrations. Our preliminary mechanistic studies revealed that SZUH280 hampers DNA damage repair in cancer cells, promoting cellular radiosensitization. In mice, a single SZUH280 dose induced rapid and prolonged HDAC8 protein degradation in xenograft tumor tissues. Moreover, SZUH280 alone or in combination with irradiation resulted in long-lasting tumor regression in an A549 tumor mouse model. Our findings qualify a new chemical tool for HDAC8 knockdown and may lead to the development of a new class of cancer therapeutics.

PROTAC chemical probes for histone deacetylase enzymes

“…A number of studies have now been reported on the PROTAC mediated degradation of HDAC8. [63][64][65][66][67][68] Again, this perhaps reflects the observation in the proteomic study by Xiong et al that HDAC8 is one of the HDAC isoforms more prone to PROTAC mediated degradation along with HDAC3 and HDAC6. Utilising a previously developed selective HDAC8 inhibitor Chotitumnavee et al were able to synthesise a selective PRO-TAC degrader of HDAC8 (Chart 3).…”

“…66 15 HDAC8 DC 50 = 0.58 mM in A549 cells. 67 still outperformed the selective HDAC8 inhibitor from which it was derived and also inhibited migration of MDA-MB-231 cells whereby the selective HDAC8 inhibitor did not. In cell viability assays, and assays investigating apoptosis, 16 was more effective than its parent selective HDAC8 inhibitor.…”

“…53 To date, a number of PROTACs have been reported capable of degrading class I HDACs. [54][55][56][57][58][59][60][61][62][63][64][65][66][67][68] PROTACs targeting HDAC1 and HDAC2…”

The Histone Deacetylase Family: Structural Features and Application of Combined Computational Methods

“…Nevertheless, some PROTACs demonstrated selectivity in degrading specific HDAC isoforms, like HDAC3, exemplified by the synthesis reported by Xiao et al of an HDAC3-selective degrader exhibiting significant potency in breast cancer cells [172][173][174][175]. Moreover, several studies have investigated the PROTACmediated degradation of HDAC8 [176][177][178][179][180], highlighting its propensity for degradation alongside HDAC3 and HDAC6, with Chotitumnavee et al developing a selective HDAC8 PROTAC that outperformed its parent inhibitor in compromising cell viability [177].…”

A cocktail therapeutic strategy based on clofarabine-containing aptamer-PROTAC for enhanced cancer therapy

“…In contrast, ApTCs treatments didn't increase the portion of cell population in S phase but showed a notable G2/ M phase arrest at 39.9% in HeLa cells (p o 0.01), which was also observed in previous small-molecule based degrader. 16 These findings indicated that the S phase arrest may contribute to the synergism of ApTCs-3X-mediated NCL degradation with clofarabine-based chemotherapy. Overall, these results demonstrate that ApTCs-3X exhibits enhanced antiproliferation, pro-apoptotic and cycle arrest potencies, acting as a potential synergistic agent for cancer therapy.…”