Small molecule modulators of KSR-bound MEK

Inventors

Dar, Arvin • Scopton, Alexander P. • Yerabolu, Jayasudhan Reddy • Khan, Zaigham M. • Real, Alexander Michael • Marsiglia, William Michael

Assignees

Icahn School of Medicine at Mount Sinai

Abstract

An ATP non-competitive inhibitor of mitogen-activated protein kinase (MEK), inter alia, human MEK (MEK1 or MEK2) having the properties: (i) allosterically binds an inhibitor pocket formed at an interaction interface between human MEK (MEK1 or MEK2) and human Kinase Suppressor of Ras (KSR1 or KSR2 or BRAF) adjacent to ATP in a physiological complex between MEK and KSR (or BRAF), forming an inhibitor-inhibitor pocket complex; (ii) is an ATP non-competitive kinase inhibitor; (iii) a structure such that when bound to the inhibitor-inhibitor pocket complex, the complex comprises the structural elements: (a) at least one moiety of the inhibitor engaging A825 of KSR1, or P878 of KSR2; or R662 of BRAF (b) at least one moiety engaging R234 of MEK, wherein where R234 is within 5 Å from any atoms of KSR1 or KSR2 or BRAF is disclosed.

Core Innovation

The invention provides an ATP non-competitive inhibitor of mitogen-activated protein kinase (MEK/MAPK) having a specified structure. The inhibitor allosterically binds an inhibitor pocket at the MEK–KSR or MEK–BRAF interface adjacent to ATP to form an inhibitor–inhibitor pocket complex, and the binding involves KSR residues A825 or P878, or BRAF residue R662, together with a MEK residue R234.

The disclosure describes a tetrahydropyrido[4,3-d]pyrimidine-2,4,7-trione scaffold substituted with a 2-fluoro-4-iodophenylamino group, a cyclopropyl substituent, and additional amide, triazole-acetamide, sulfonamide, and other polar solubilizing groups. It further includes hydrophobic, aromatic, and heteroatom-containing substituent classes, including fluoroalkyl/haloalkyl, alkyl, heteroalkyl, cycloalkyl, aryl, and heteroaryl with 1–34 heteroatoms.

Linker options are specified to support a δ motif and include amide and sulfamide linkers, including an L–δ motif sulfamide motif. The disclosure further includes pharmaceutical formulation aspects using a pharmaceutically acceptable carrier and framework assay definitions for detecting target engagement of MEK–KSR complexes using methods including surface plasmon resonance (BIAcore), high throughput screening (HTS), FRET/energy transfer, and scintillation proximity assay (SPA).

The patent supports the compound series with X-ray structures, LC-MS, and NMR characterization, and reports interface remodeling of the MEKi allosteric pocket. Trametinib is described as having unexpected direct KSR engagement, supporting the trametiglue concept, and selectivity versus RAF-bound MEK is described using a bump-and-hole concept at pre-αG loops.

Claims Coverage

The consolidated claim set centers on one independent claim covering an ATP non-competitive inhibitor of mitogen-activated protein kinase having a specified structure, with dependent refinements to pharmaceutically acceptable salts and enantiomers. In total, three inventive features are presented.

Coverage centers on an ATP non-competitive MEK/MAPK inhibitor defined by a specified structure, with additional scope for pharmaceutically acceptable salts and enantiomeric forms.

Stated Advantages

Documented Applications