{"doi":"10.1016/j.tips.2020.08.008","title":"Nanoformulation of BRD4-Degrading PROTAC: Improving Druggability To Target the ‘Undruggable’ MYC in Pancreatic Cancer","abstract":"In a recent study, Saraswat and colleagues identified a novel proteolysis targeting chimera (PROTAC), ARV-825 (ARV), that efficiently degrades bromodomain-containing protein 4 (BRD4) to drug the ‘undruggable’ MYC in pancreatic cancer. ARV-loaded polyethylene glycol–poly lactic acid-co-glycolic acid (PLGA–PEG) polymeric nanoparticles (ARV-NPs) showed promising anticancer activity in both 2D cell culture and 3D multicellular tumor spheroid models of pancreatic cancer. This study demonstrates a unique therapeutic strategy in which targeting BRD4 for degradation via the E3 ubiquitin ligase cereblon (CRBN) pathway leads to sustained inhibition of oncogenic MYC expression for effective treatment of pancreatic cancer. In a recent study, Saraswat and colleagues identified a novel proteolysis targeting chimera (PROTAC), ARV-825 (ARV), that efficiently degrades bromodomain-containing protein 4 (BRD4) to drug the ‘undruggable’ MYC in pancreatic cancer. ARV-loaded polyethylene glycol–poly lactic acid-co-glycolic acid (PLGA–PEG) polymeric nanoparticles (ARV-NPs) showed promising anticancer activity in both 2D cell culture and 3D multicellular tumor spheroid models of pancreatic cancer. This study demonstrates a unique therapeutic strategy in which targeting BRD4 for degradation via the E3 ubiquitin ligase cereblon (CRBN) pathway leads to sustained inhibition of oncogenic MYC expression for effective treatment of pancreatic cancer. Pancreatic cancer is a highly fatal human cancer. Mutation of the KRAS oncogene is the signature genetic event in pancreatic cancer that deregulates cell proliferation as well as apoptosis by activating several signaling pathways [1.Haeberle L. Esposito I. Pathology of pancreatic cancer.Transl. Gastroenterol. Hepatol. 2019; 4: 50Crossref PubMed Scopus (51) Google Scholar]. The prevalence of ‘undruggable’ KRAS drivers and signaling pathway activation contributes to KRAS-mediated drug resistance in pancreatic cancer [2.Fan Z. et al.Critical role of KRAS mutation in pancreatic ductal adenocarcinoma.Translat. Cancer Res. 2018; 7: 1728-1736Crossref Scopus (7) Google Scholar]. This eventually leads to expression of the oncogenic MYC gene, an essential downstream effector of KRAS in pancreatic cancer. The direct link between oncogenic MYC and KRAS drivers raises the possibility that inhibition of MYC expression could be an effective therapeutic strategy for KRAS-mutant tumors such as pancreatic cancer [3.Korc M. Beyond Kras: MYC rules in pancreatic cancer.Cell. Mol. Gastroenterol. Hepatol. 2018; 6: 223-224Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar]. Transcriptional coactivator BRD4 is a member of the bromodomain and extra-terminal domain (BET) family, and a driver of oncogenesis that activates MYC transcription; by destabilizing the MYC protein via phosphorylation, subsequently leading to ubiquitination and degradation, homeostatic levels of c-MYC protein are maintained. Small-molecule BET inhibitors such as JQ1 reduce MYC transcription but have no effect on MYC protein stability [4.Devaiah B.N. et al.MYC protein stability is negatively regulated by BRD4.Proc. Natl. Acad. Sci. U. S. A. 2020; 117: 13457-13467Crossref PubMed Scopus (25) Google Scholar]. Owing to the reversible nature of binding of JQ1 to BET, as well as its short half-life, there is a need to identify molecules that would directly degrade the target BRD4 protein instead of merely inhibiting it [5.Wroblewski M. et al.BET-inhibition by JQ1 promotes proliferation and self-renewal capacity of hematopoietic stem cells.Haematologica. 2018; 103: 939-948Crossref PubMed Scopus (15) Google Scholar,6.Maggisano V. et al.Nanoparticles loaded with the BET inhibitor JQ1 block the growth of triple negative breast cancer cells in vitro and in vivo.Cancers. 2019; 12: 91Crossref Scopus (11) Google Scholar]. PROTACs are engineered bifunctional molecules composed of a target-binding ligand joined via a linker to an effector ligand, pomalidomide, that bi","journal":"Trends in Pharmacological Sciences","year":2020,"id":58899,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":70,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9517,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":235166,"name":"Tamara Minko","orcid":"0000-0002-1633-4705","position":0,"is_corresponding":true}],"reference_count":15,"raw_metadata":null,"created_at":"2026-07-18T21:07:33.416320Z","pmid":"32893006","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}