UM171

UM171

Clinical data
Pregnancy category	d
Identifiers
IUPAC name trans-4-N-[2-benzyl-7-(2-methyltetrazol-5-yl)-9H-pyrimido[4,5-b]indol-4-yl]cyclohexane-1,4-diamine
CAS Number	1448724-09-1
PubChem CID	71714981
Chemical and physical data
Formula	C25H27N9
Molar mass	453.554 g·mol−1
3D model (JSmol)	Interactive image
SMILES CN1N=C(N=N1)C2=CC3=C(C=C2)C4=C(N3)N=C(N=C4NC5CCC(CC5)N)CC6=CC=CC=C6
InChI 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 small molecule that was initially developed to facilitate the ex vivo expansion of hematopoietic stem and progenitor cells (HSPCs), but is now also being evaluated for potential anti-cancer activity.

UM171 was first identified in 2014 during a chemical screening campaign aimed at finding compounds that promote the ex vivo expansion of HSPCs. ^[1] It was shown to markedly increase the number of transplantable stem cells derived from cord blood, which led to rapid preclinical and clinical testing in the context of hematopoietic stem cell transplantation. ^{[2] [3] [4] [5] [6]}

More recently, UM171 has been investigated for its potential in cancer therapy. Since suppression of LSD1 activity has emerged as a promising strategy in oncology, UM171—which promotes the ubiquitin-dependent proteasomal degradation of the LSD1–CoREST complex—has shown anti-cancer effects in preclinical studies. ^{[7] [8] [9] [10] [11] [12] [13]}

Mechanistic studies have shown that UM171 targets HDAC1 and HDAC2 within the LSD1/CoREST complex for degradation. Acting as a molecular glue, UM171 promotes the interaction of the CUL3–KBTBD4 E3 ligase with HDAC1/2, leading to their ubiquitination and selective degradation. This, in turn, destabilizes HDAC1/2-containing corepressors such as CoREST and MIER1. Although LSD1 and CoREST are also degraded, these effects occur secondarily and more slowly compared to the direct depletion of HDAC1/2. ^[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. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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 . PMC   11882444 . PMID   39939761.