Abstract
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. 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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
-
Animals
-
Caco-2 Cells
-
Cell Proliferation / drug effects
-
Cell Survival / drug effects
-
Disease Models, Animal
-
Dose-Response Relationship, Drug
-
Female
-
Histone-Lysine N-Methyltransferase / chemistry
-
Histone-Lysine N-Methyltransferase / metabolism*
-
Humans
-
Injections, Intraventricular
-
Leukemia, Myeloid, Acute / drug therapy
-
Leukemia, Myeloid, Acute / metabolism*
-
Mice
-
Mice, Inbred C57BL
-
Mice, SCID
-
Models, Molecular
-
Molecular Structure
-
Myeloid-Lymphoid Leukemia Protein / chemistry
-
Myeloid-Lymphoid Leukemia Protein / metabolism*
-
Protein Binding / drug effects
-
Proto-Oncogene Proteins / chemistry
-
Proto-Oncogene Proteins / metabolism*
-
Pyrimidines / administration & dosage
-
Pyrimidines / chemistry
-
Pyrimidines / pharmacology*
-
Small Molecule Libraries / administration & dosage
-
Small Molecule Libraries / chemistry
-
Small Molecule Libraries / pharmacology*
-
Structure-Activity Relationship
-
Thiophenes / administration & dosage
-
Thiophenes / chemistry
-
Thiophenes / pharmacology*
Substances
-
KMT2A protein, human
-
MEN1 protein, human
-
MI-538
-
Proto-Oncogene Proteins
-
Pyrimidines
-
Small Molecule Libraries
-
Thiophenes
-
Myeloid-Lymphoid Leukemia Protein
-
Histone-Lysine N-Methyltransferase