UM171

Last updated

UM171
UM171 structure.png
Clinical data
Pregnancy
category
  • d
Identifiers
  • trans-4-N-[2-benzyl-7-(2-methyltetrazol-5-yl)-9H-pyrimido[4,5-b]indol-4-yl]cyclohexane-1,4-diamine
CAS Number
PubChem CID
Chemical and physical data
Formula C25H27N9
Molar mass 453.554 g·mol−1
3D model (JSmol)
  • CN1N=C(N=N1)C2=CC3=C(C=C2)C4=C(N3)N=C(N=C4NC5CCC(CC5)N)CC6=CC=CC=C6
  • InChI=1S/C25H27N9/c1-34-32-23(31-33-34)16-7-12-19-20(14-16)28-25-22(19)24(27-18-10-8-17(26)9-11-18)29-21(30-25)13-15-5-3-2-4-6-15/h2-7,12,14,17-18H,8-11,13,26H2,1H3,(H2,27,28,29,30)
  • Key:AZXXGVPWWKWGAE-UHFFFAOYSA-N

UM171 is a drug which acts as a small-molecule degrader of the enzyme lysine-specific demethylase 1 (LSD1). [1] [2] [3] [4] [5] It was originally discovered as an inducer of the proliferation of hematopoietic stem cells, a function which makes it useful for the treatment of various blood disorders. [6] [7] [8] [9] [10] However more recently it has been found that suppression of LSD1 activity is also useful for the treatment of some forms of cancer, and so UM171 is now being investigated for anti-cancer applications as well. [11] [12] [13] [14]

References

  1. ↑ Fares I, Chagaroui J, Gareau Y, Gingras S, Mayotte N, Csaszar E, et al. (December 6, 2014). "Pyrimido-Indole Derivatives Are Novel Agonists of Human Cord Blood Hematopoietic Stem Cell Self-Renewal". Blood. 124 (21): 650. doi:10.1182/blood.V124.21.650.650.
  2. ↑ Feng Y, Xie XY, Yang YQ, Sun YT, Ma WH, Zhou PJ, et al. (July 2019). "Synthesis and evaluation of pyrimidoindole analogs in umbilical cord blood ex vivo expansion". European Journal of Medicinal Chemistry. 174: 181–197. doi:10.1016/j.ejmech.2019.04.042. PMID   31035239.
  3. ↑ Subramaniam A, Žemaitis K, Talkhoncheh MS, Yudovich D, Bäckström A, Debnath S, et al. (November 2020). "Lysine-specific demethylase 1A restricts ex vivo propagation of human HSCs and is a target of UM171". Blood. 136 (19): 2151–2161. doi:10.1182/blood.2020005827. PMC   7645986 . PMID   32582923.
  4. ↑ Coulombe P, Tomellini E, Chagraoui J, Mayotte N, Sauvageau G (January 2025). "Deciphering the effect of UM171 on human hematopoietic progenitor cell fate through clonal analysis". Nature Communications. 16 (1): 195. doi:10.1038/s41467-024-55225-7. PMC   11696577 . PMID   39747844.
  5. ↑ Yeo MJ, Zhang O, Xie X, Nam E, Payne NC, Gosavi PM, et al. (February 2025). "UM171 glues asymmetric CRL3-HDAC1/2 assembly to degrade CoREST corepressors". Nature. doi:10.1038/s41586-024-08532-4. PMID   39939761.
  6. ↑ Xuan J, Liu Y, Liu J, Zeng X, Wang H (May 2022). "New Insights into Hematopoietic Stem Cell Expansion to Stimulate Repopulation of the Adult Blood System for Transplantation". Life. 12 (5): 716. Bibcode:2022Life...12..716X. doi: 10.3390/life12050716 . PMC   9146250 . PMID   35629383.
  7. ↑ Huang X, Guo B (July 2022). "Update on preclinical and clinical efforts on ex-vivo expansion of hematopoietic stem and progenitor cells". Current Opinion in Hematology. 29 (4): 167–173. doi:10.1097/MOH.0000000000000714. PMID   35220322.
  8. ↑ Cohen S, Bambace N, Ahmad I, Roy J, Tang X, Zhang MJ, et al. (October 2023). "Improved outcomes of UM171-expanded cord blood transplantation compared with other graft sources: real-world evidence". Blood Advances. 7 (19): 5717–5726. doi:10.1182/bloodadvances.2023010599. PMC   10539875 . PMID   37467030.
  9. ↑ Liu B, Klatt D, Zhou Y, Manis JP, Sauvageau G, Pellin D, et al. (November 2024). "UM171 enhances fitness and engraftment of gene-modified hematopoietic stem cells from patients with sickle cell disease". Blood Advances. 8 (22): 5885–5895. doi:10.1182/bloodadvances.2024013932. PMC   11612367 . PMID   39293082.
  10. ↑ Cui Y, Ren Y, Ren F, Zhang Y, Wang H (December 2024). "Synergistic effect and molecular mechanism of nicotinamide and UM171 in ex vivo expansion of long-term hematopoietic stem cells". Regenerative Therapy. 27: 191–199. doi:10.1016/j.reth.2024.03.011. PMC   11150914 . PMID   38840730.
  11. ↑ Hu A, Gao J, Varier KM, Gajendran B, Jiang F, Liu W, et al. (November 2022). "UM171 cooperates with PIM1 inhibitors to restrict HSC expansion markers and suppress leukemia progression". Cell Death Discovery. 8 (1): 448. doi:10.1038/s41420-022-01244-6. PMC   9637110 . PMID   36335089.
  12. ↑ Ran X, Hu A, Kuang Y, Wang C, Liu W, Xiao X, et al. (September 2024). "UM171 suppresses breast cancer progression by inducing KLF2". Breast Cancer Research and Treatment. 207 (2): 405–415. doi:10.1007/s10549-024-07372-0. PMC   11297059 . PMID   38874684.
  13. ↑ Li M, Dai M, Cheng B, Li S, Guo E, Fu J, et al. (April 2024). "Strategies that regulate LSD1 for novel therapeutics". Acta Pharmaceutica Sinica. B. 14 (4): 1494–1507. doi:10.1016/j.apsb.2024.01.005. PMC   10985039 . PMID   38572094.
  14. ↑ Song Y, Yu B (February 2025). "Leveraging non-enzymatic functions of LSD1 for novel therapeutics". Trends in Pharmacological Sciences. doi:10.1016/j.tips.2025.01.006. PMID   39966067.
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