Chemistry:JQ1

From HandWiki

JQ1 is a thienotriazolodiazepine and a potent inhibitor of the BET family of bromodomain proteins which include BRD2, BRD3, BRD4, and the testis-specific protein BRDT in mammals. BET inhibitors structurally similar to JQ1 are being tested in clinical trials for a variety of cancers including NUT midline carcinoma.[1] It was developed by the James Bradner laboratory at Brigham and Women's Hospital and named after chemist Jun Qi. The chemical structure was inspired by patent of similar BET inhibitors by Mitsubishi Tanabe Pharma.[2] Structurally it is related to benzodiazepines. While widely used in laboratory applications, JQ1 is not itself being used in human clinical trials because it has a short half-life.

Efficacy in mouse models of cancer

Interest in JQ1 as a cancer therapeutic stemmed from its ability to inhibit BRD4 and BRD3, both of which form fusion oncogenes that drive NUT midline carcinoma.[3][4] Subsequent work demonstrated that a number of cancers including some forms of acute myelogenous leukemia (AML), multiple myeloma (MM), and acute lymphoblastic leukemia (ALL) were also highly sensitive to BET inhibitors.[5][6]

In other applications

JQ1 has also been investigated for other applications in the treatment of HIV infection,[7] as a male contraceptive,[8] and in slowing the progression of heart disease.[9]

JQ1 has been functionalized in numerous different studies of targeted protein degradation. For example, conjugation of JQ1 to phthalimide moieties such as that found in thalidomide recruits the E3 ubiquitin ligase cereblon (CRBN) to effect proteasomal degradation of BRD4.[10] Monovalent degraders based on functionalizing JQ1 have also been discovered.[11][12][13][14]

Fusion of JQ1 to other molecules targeting specific genomic loci has been demonstrated to rewire transcription.[15][16]

See also

References

  1. ↑ "Studies found for: bet inhibitor". ClinicalTrials.Gov. National Library of Medicine, National Institutes of Health, U.S. Department of Health and Human Services. https://www.clinicaltrials.gov/ct2/results?term=bet+inhibitor&Search=Search. 
  2. ↑ WO/2009/084693
  3. ↑ "Selective inhibition of BET bromodomains". Nature 468 (7327): 1067–73. December 2010. doi:10.1038/nature09504. PMID 20871596. Bibcode: 2010Natur.468.1067F. 
  4. ↑ "Differentiation of NUT midline carcinoma by epigenomic reprogramming". Cancer Research 71 (7): 2686–96. April 2011. doi:10.1158/0008-5472.CAN-10-3513. PMID 21447744. 
  5. ↑ "BET domain co-regulators in obesity, inflammation and cancer". Nature Reviews. Cancer 12 (7): 465–77. June 2012. doi:10.1038/nrc3256. PMID 22722403. "The mechanisms behind the therapeutic activity of BET bromodomain inhibition". Molecular Cell 54 (5): 728–36. June 2014. doi:10.1016/j.molcel.2014.05.016. PMID 24905006. 
  6. ↑ "BET inhibition as a single or combined therapeutic approach in primary paediatric B-precursor acute lymphoblastic leukaemia". Blood Cancer Journal 3 (7): e126. July 2013. doi:10.1038/bcj.2013.24. PMID 23872705. 
  7. ↑ "BET bromodomain inhibition as a novel strategy for reactivation of HIV-1". Journal of Leukocyte Biology 92 (6): 1147–54. December 2012. doi:10.1189/jlb.0312165. PMID 22802445. 
  8. ↑ "Small-molecule inhibition of BRDT for male contraception". Cell 150 (4): 673–84. August 2012. doi:10.1016/j.cell.2012.06.045. PMID 22901802. 
  9. ↑ "BET bromodomains mediate transcriptional pause release in heart failure". Cell 154 (3): 569–82. August 2013. doi:10.1016/j.cell.2013.07.013. PMID 23911322. 
  10. ↑ "DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation". Science 348 (6241): 1376–1381. June 2015. doi:10.1126/science.aab1433. PMID 25999370. 
  11. ↑ "Abstract 4452: GNE-0011, a novel monovalent BRD4 degrader" (in en). Cancer Research 79 (13_Supplement): 4452. 2019-07-01. doi:10.1158/1538-7445.AM2019-4452. ISSN 0008-5472. https://aacrjournals.org/cancerres/article/79/13_Supplement/4452/636335/Abstract-4452-GNE-0011-a-novel-monovalent-BRD4. 
  12. ↑ "Targeted protein degradation via intramolecular bivalent glues". Nature 627 (8002): 204–211. March 2024. doi:10.1038/s41586-024-07089-6. PMID 38383787. 
  13. ↑ "DCAF16-Based Covalent Handle for the Rational Design of Monovalent Degraders". ACS Central Science 10 (7): 1318–1331. July 2024. doi:10.1021/acscentsci.4c00286. PMID 39071058. 
  14. ↑ "CRISPR Screen Reveals BRD2/4 Molecular Glue-like Degrader via Recruitment of DCAF16". ACS Chemical Biology 18 (2): 331–339. February 2023. doi:10.1021/acschembio.2c00747. PMID 36656921. 
  15. ↑ "Synthetic transcription elongation factors license transcription across repressive chromatin". Science 358 (6370): 1617–1622. December 2017. doi:10.1126/science.aan6414. PMID 29192133. 
  16. ↑ "Rewiring cancer drivers to activate apoptosis". Nature 620 (7973): 417–425. August 2023. doi:10.1038/s41586-023-06348-2. PMID 37495688. 



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