2. Academic Validation
  3. Progress towards small molecule menin-mixed lineage leukemia (MLL) interaction inhibitors with in vivo utility

Progress towards small molecule menin-mixed lineage leukemia (MLL) interaction inhibitors with in vivo utility

  • Bioorg Med Chem Lett. 2015 Jul 1;25(13):2720-5. doi: 10.1016/j.bmcl.2015.04.026.
Timothy Senter 1,  Rocco D Gogliotti 2,  Changho Han 2,  Charles W Locuson 2,  Ryan Morrison 2,  J Scott Daniels 3,  Tomasz Cierpicki 4,  Jolanta Grembecka 4,  Craig W Lindsley 5,  Shaun R Stauffer 6
Affiliations

Affiliations

  • 1 Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
  • 2 Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
  • 3 Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Department of Pathology, University of Michigan, Ann Arbor, 1150 West Medical Center Drive, MSRBI, Room 4510D, MI 48109, USA.
  • 4 Department of Pathology, University of Michigan, Ann Arbor, 1150 West Medical Center Drive, MSRBI, Room 4510D, MI 48109, USA.
  • 5 Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA; Department of Pathology, University of Michigan, Ann Arbor, 1150 West Medical Center Drive, MSRBI, Room 4510D, MI 48109, USA.
  • 6 Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA; Department of Pathology, University of Michigan, Ann Arbor, 1150 West Medical Center Drive, MSRBI, Room 4510D, MI 48109, USA. Electronic address: [email protected].
PMID: 25987377 DOI: 10.1016/j.bmcl.2015.04.026
Abstract

A series of substituted hydroxymethyl piperidine small molecule inhibitors of the protein-protein interaction between menin and mixed lineage leukemia 1 (MLL1) are described. Initial members of the series showed good inhibitory disruption of the menin-MLL1 interaction but demonstrated poor physicochemical and DMPK properties. Utilizing a structure-guided and iterative optimization approach key substituents were optimized leading to inhibitors with cell-based activity, improved in vitro DMPK parameters, and improved half-lives in rodent PK studies leading to MLPCN probe ML399. Ancillary off-target activity remains a parameter for further optimization.

Keywords

ML399; Menin; Mixed lineage leukemia (MLL); Protein–protein interaction.

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