Property Focused Structure-Based Optimization of Small Molecule Inhibitors of the Protein–Protein Interaction between Menin and Mixed Lineage Leukemia (MLL)

Borkin, Dmitry; Pollock, Jonathan; Kempinska, Katarzyna; Purohit, Trupta; Li, Xiaoqin; Wen, Bo; Zhao, Ting; Miao, Hongzhi; Shukla, Shirish; He, Miao; Sun, Duxin; Cierpicki, Tomasz; Grembecka, Jolanta

doi:10.1021/acs.jmedchem.5b01305

Title: Property Focused Structure-Based Optimization of Small Molecule Inhibitors of the Protein–Protein Interaction between Menin and Mixed Lineage Leukemia (MLL)

Journal Article · 24 January 2016 · Journal of Medicinal Chemistry

DOI: https://doi.org/10.1021/acs.jmedchem.5b01305 · OSTI ID:1498394

Borkin, Dmitry ^[1]; Pollock, Jonathan ^[1]; Kempinska, Katarzyna ^[1]; Purohit, Trupta ^[1]; Li, Xiaoqin ^[1]; Wen, Bo ^[1]; Zhao, Ting ^[1]; Miao, Hongzhi ^[1]; Shukla, Shirish ^[1]; He, Miao ^[1]; Sun, Duxin ^[1]; Cierpicki, Tomasz ^[1]; Grembecka, Jolanta ^[1]

Univ. of Michigan, Ann Arbor, MI (United States)

Development of potent small molecule inhibitors of protein–protein interactions with optimized druglike properties represents a challenging task in lead optimization process. Here, we report synthesis and structure-based optimization of new thienopyrimidine class of compounds, which block the protein–protein interaction between menin and MLL fusion proteins that plays an important role in acute leukemias with MLL translocations. We performed simultaneous optimization of both activity and druglike properties through systematic exploration of substituents introduced to the indole ring of lead compound 1 (MI-136) to identify compounds suitable for in vivo studies in mice. We report this work resulted in the identification of compound 27 (MI-538), which showed significantly increased activity, selectivity, polarity, and pharmacokinetic profile over 1 and demonstrated a pronounced effect in a mouse model of MLL leukemia. This study, which reports detailed structure–activity and structure–property relationships for the menin–MLL inhibitors, demonstrates challenges in optimizing inhibitors of protein–protein interactions for potential therapeutic applications.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: American Cancer Society; Leukemia and Lymphoma Society; Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor; National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); University of Michigan

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1498394

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 3 Vol. 59; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Novel agents for the treatment of childhood leukemia: an update Eryılmaz, Ertugrul; Canpolat, Cengiz OncoTargets and Therapy, Vol. Volume 10 https://doi.org/10.2147/ott.s126368	journal	July 2017
Targeting histone methyltransferase and demethylase in acute myeloid leukemia therapy Castelli, Germana; Pelosi, Elvira; Testa, Ugo OncoTargets and Therapy, Vol. Volume 11 https://doi.org/10.2147/ott.s145971	journal	December 2017
MLL-Rearranged Leukemias—An Update on Science and Clinical Approaches Winters, Amanda C.; Bernt, Kathrin M. Frontiers in Pediatrics, Vol. 5 https://doi.org/10.3389/fped.2017.00004	journal	February 2017
Targeting transcription factors in cancer — from undruggable to reality Bushweller, John H. Nature Reviews Cancer, Vol. 19, Issue 11 https://doi.org/10.1038/s41568-019-0196-7	journal	September 2019
Menin inhibitor MI-3454 induces remission in MLL1-rearranged and NPM1-mutated models of leukemia Klossowski, Szymon; Miao, Hongzhi; Kempinska, Katarzyna Journal of Clinical Investigation, Vol. 130, Issue 2 https://doi.org/10.1172/jci129126	journal	December 2019
Co-inhibition of HDAC and MLL-menin interaction targets MLL-rearranged acute myeloid leukemia cells via disruption of DNA damage checkpoint and DNA repair Ye, Jing; Zha, Jie; Shi, Yuanfei Clinical Epigenetics, Vol. 11, Issue 1 https://doi.org/10.1186/s13148-019-0723-0	journal	October 2019
Using Structural Analysis In Silico to Assess the Impact of Missense Variants in MEN1 Caswell, Richard C.; Owens, Martina M.; Gunning, Adam C. Journal of the Endocrine Society, Vol. 3, Issue 12 https://doi.org/10.1210/js.2019-00260	journal	September 2019
MLL-Rearranged Leukemias—An Update on Science and Clinical Approaches Winters, Amanda C.; Bernt, Kathrin M. Frontiers in Pediatrics, Vol. 5 https://doi.org/10.3389/fped.2017.00004	journal	February 2017
Direct and Indirect Targeting of HOXA9 Transcription Factor in Acute Myeloid Leukemia. Cancers, Vol. 11, Issue 6 https://doi.org/10.3390/cancers11060837	journal	June 2019
BindingDB Entry 50047242: Property Focused Structure-Based Optimization of Small Molecule Inhibitors of the Protein-Protein Interaction between Menin and Mixed Lineage Leukemia (MLL). BindingDB https://doi.org/10.7270/q2m32xm7	dataset	January 2017

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Title: Property Focused Structure-Based Optimization of Small Molecule Inhibitors of the Protein–Protein Interaction between Menin and Mixed Lineage Leukemia (MLL)

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