ARV-771 Acts as an Inducer of Cell Cycle Arrest and Apoptosis to Suppress Hepatocellular Carcinoma Progression

Abstract

Hepatocellular carcinoma (HCC) is the most commonly diagnosed liver cancer with limited treatment options and extremely poor prognosis worldwide. Recently, the proteolysis targeting chimeras (PROTACs), which aim to induce proteasome-mediated degradation of interesting proteins via recruiting E3 ligases, have become the advanced tools and attractive molecules for cancer treatment. However, the anticancer effects of PROTACs in HCC remain to be clarified. Here, we evaluate the anticancer activity of ARV-771, a previously reported PROTAC compound designed for bromodomain and extra-terminal domain (BET) proteins, in HCC. We show that ARV-771 suppresses the cell viability and colony formation of HCC cells via arresting cell cycle progression and triggering apoptosis. Further investigations reveal that ARV-771 notably downregulates multiple non-proteasomal deubiquitinases which are critical to the development of cancers. Additionally, HCC cells can decrease their sensitivity to ARV-771 via activating the MEK/ERK and p38 MAPKs. ARV-771 also inhibits HCC progression in vivo. Moreover, we show that ARV-771 and sorafenib, a Raf inhibitor that clinically used for targeted therapy of liver cancer, can synergistically inhibit the growth of HCC cells. Overall, this study not only explores the anticancer activity of ARV-771 and its underlying mechanisms in HCC, but also deepens our understanding of deubiquitinases, MAPKs, cell cycle, and apoptosis induction in cancer therapy.

Unlocking Cellular Control: The Promise of PROTACs in Disease Intervention

“…[27] [30] The superiority of a BET-PROTAC compared to BET inhibitor is shown by the observation that ARV-771 induces apoptosis in CRPC cells grown in-vitro, whereas JQ-1(Thienotriazolodiazepine and a potent inhibitor of the BET family) and OTX015 (Birabresib, an experimental small molecule inhibitor of BRD2, BRD3, and BRD4) have a minor effect. The 80% tumor growth inhibition that occurs in mice treated with OTX015 is induced by ARV-771.…”

PROTACs in Epigenetic Cancer Therapy: Current Status and Future Opportunities

“…In prostate cancer cells, ARV-771 could restrain androgen receptor signaling and androgen receptor levels to inhibit tumor growth [ 56 , 57 ]. Subsequently, in liver cancer, non-small-cell lung cancer, and esophageal squamous cell carcinoma cell lines, ARV-771 could inhibit the cell viability of tumor cells by preventing cell cycle progression and triggering apoptosis, resulting in the development of a cisplatin and radiological screening program for non-small-cell lung cancer, possibly creating the most promising anticancer drugs [ 58 , 59 , 60 ]. ARV-771 was also shown to form a folate protein complex with the folate group that could minimize potential toxicity in a tissue-selective manner [ 61 ].…”

A Versatile and Sustainable Multicomponent Platform for the Synthesis of Protein Degraders: Proof-of-Concept Application to BRD4-Degrading PROTACs

“…1 H NMR (400 MHz; CDCl 3 ): δ 7.82 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 4.19 (t, J = 5.8 Hz, 2H), 3.51 (t, J = 5.8 Hz, 2H), 2.48 (s, 3H), 2.05 (quint, J = 5.8 Hz, 2H). 13 4-Isocyanobutyl 4-Methylbenzenesulfonate (17). The title compound was synthesized following the general procedure A.…”

“…BET proteins include BRD2, BRD3, BRD4, and BRDT and recruit transcriptional complexes by binding to acetylated lysine residues on histones, thereby controlling genes involved in cellular proliferation and cell cycle progression. Because alterations in the regulation of activities by BET proteins, especially BRD4, 12 are associated with different inflammatory diseases and cancer, several BET degraders, including dBET1, 13 MZ1, 14 dBET21, 15,16 and ARV-771 17 (Figure 3) bearing (+)-JQ1 18,19 as a warhead, have been developed, with the ultimate goal of finding more effective treatments compared to small-molecule inhibitors. 18−20 From a structural point of view, while a large variety of warheads have been explored to bind different POIs, independently from their mechanism of action, cereblon (CRBN) targeting ligands (i.e., immunomodulatory imide drug (IMiD)-based ligands, such as thalidomide and its structural analogues) 21 and Von Hippel-Lindau (VHL) targeting ligands (i.e., hydroxyproline-based molecules) are the most commonly used anchors to recruit E3 ligases (Figure 1).…”

“…BET proteins include BRD2, BRD3, BRD4, and BRDT and recruit transcriptional complexes by binding to acetylated lysine residues on histones, thereby controlling genes involved in cellular proliferation and cell cycle progression. Because alterations in the regulation of activities by BET proteins, especially BRD4, are associated with different inflammatory diseases and cancer, several BET degraders, including dBET1, MZ1, dBET21, , and ARV-771 (Figure ) bearing (+)-JQ1 , as a warhead, have been developed, with the ultimate goal of finding more effective treatments compared to small-molecule inhibitors. − …”