title: Progress towards small molecule menin-mixed lineage leukemia (MLL) interaction inhibitors with in vivo utility.
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.
authors.affiliation: 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.
authors.forename: Timothy
authors.initials: T
authors.lastname: Senter
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
authors.forename: Rocco D
authors.initials: RD
authors.lastname: Gogliotti
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
authors.forename: Changho
authors.initials: C
authors.lastname: Han
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Locuson
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Morrison
authors.affiliation: 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.
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, 1150 West Medical Center Drive, MSRBI, Room 4510D, MI 48109, USA.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Cierpicki
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, 1150 West Medical Center Drive, MSRBI, Room 4510D, MI 48109, USA.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Grembecka
authors.affiliation: 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.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.affiliation: 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: shaun.stauffer@vanderbilt.edu.
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Stauffer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008958:Models, Molecular; D051788:Myeloid-Lymphoid Leukemia Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry; D010880:Piperidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D054730:Protein Interaction Domains and Motifs / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; C105373:MEN1 protein, human; D010880:Piperidines; D011518:Proto-Oncogene Proteins; D051788:Myeloid-Lymphoid Leukemia Protein
keywords: ML399; Menin; Mixed lineage leukemia (MLL); Protein–protein interaction