Chemistry:UM171
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
- ↑ "Pyrimido-Indole Derivatives Are Novel Agonists of Human Cord Blood Hematopoietic Stem Cell Self-Renewal". Blood 124 (21): 650. December 6, 2014. doi:10.1182/blood.V124.21.650.650. http://www.bloodjournal.org/content/124/21/650.abstract?sso-checked=true.
- ↑ "New Insights into Hematopoietic Stem Cell Expansion to Stimulate Repopulation of the Adult Blood System for Transplantation". Life 12 (5): 716. May 2022. doi:10.3390/life12050716. PMID 35629383. Bibcode: 2022Life...12..716X.
- ↑ "Update on preclinical and clinical efforts on ex-vivo expansion of hematopoietic stem and progenitor cells". Current Opinion in Hematology 29 (4): 167–173. July 2022. doi:10.1097/MOH.0000000000000714. PMID 35220322.
- ↑ "Improved outcomes of UM171-expanded cord blood transplantation compared with other graft sources: real-world evidence". Blood Advances 7 (19): 5717–5726. October 2023. doi:10.1182/bloodadvances.2023010599. PMID 37467030.
- ↑ "UM171 enhances fitness and engraftment of gene-modified hematopoietic stem cells from patients with sickle cell disease". Blood Advances 8 (22): 5885–5895. November 2024. doi:10.1182/bloodadvances.2024013932. PMID 39293082.
- ↑ "Synergistic effect and molecular mechanism of nicotinamide and UM171 in ex vivo expansion of long-term hematopoietic stem cells". Regenerative Therapy 27: 191–199. December 2024. doi:10.1016/j.reth.2024.03.011. PMID 38840730.
- ↑ "UM171 cooperates with PIM1 inhibitors to restrict HSC expansion markers and suppress leukemia progression". Cell Death Discovery 8 (1): 448. November 2022. doi:10.1038/s41420-022-01244-6. PMID 36335089.
- ↑ "UM171 suppresses breast cancer progression by inducing KLF2". Breast Cancer Research and Treatment 207 (2): 405–415. September 2024. doi:10.1007/s10549-024-07372-0. PMID 38874684.
- ↑ "Strategies that regulate LSD1 for novel therapeutics". Acta Pharmaceutica Sinica. B 14 (4): 1494–1507. April 2024. doi:10.1016/j.apsb.2024.01.005. PMID 38572094.
- ↑ "Leveraging non-enzymatic functions of LSD1 for novel therapeutics". Trends in Pharmacological Sciences. February 2025. doi:10.1016/j.tips.2025.01.006. PMID 39966067.
- ↑ "Synthesis and evaluation of pyrimidoindole analogs in umbilical cord blood ex vivo expansion". European Journal of Medicinal Chemistry 174: 181–197. July 2019. doi:10.1016/j.ejmech.2019.04.042. PMID 31035239.
- ↑ "Lysine-specific demethylase 1A restricts ex vivo propagation of human HSCs and is a target of UM171". Blood 136 (19): 2151–2161. November 2020. doi:10.1182/blood.2020005827. PMID 32582923.
- ↑ "Deciphering the effect of UM171 on human hematopoietic progenitor cell fate through clonal analysis". Nature Communications 16 (1): 195. January 2025. doi:10.1038/s41467-024-55225-7. PMID 39747844.
- ↑ "UM171 glues asymmetric CRL3-HDAC1/2 assembly to degrade CoREST corepressors". Nature. February 2025. doi:10.1038/s41586-024-08532-4. PMID 39939761.
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