Cereblon modulators and uses thereof
Inventors
Cravatt, Benjamin F. • Patricelli, Matthew • Stamos, Dean • SIMON, Gabe • HORNING, Benjamin • Weinstein, David • VINOGRADOVA, EKATERINA
Assignees
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Publication Number
US-10869860-B2
Publication Date
2020-12-22
Expiration Date
Abstract
Disclosed herein are compositions and methods for modulating cereblon neosubstrates. A small molecule modulator of Formula (I*), or a pharmaceutically acceptable salt or solvate thereof can be used to modulate cereblon neosubstrates.
Core Innovation
The disclosure relates to cereblon-targeting small-molecule modulators and related cereblon conjugates. It includes a small molecule adduct of Formula (I*), or a pharmaceutically acceptable salt or solvate thereof, defined by structural variables A, B, D, E, F, X, Y, L, Z1, and multiple R-group definitions.
A key aspect of the invention is that the sulfur atom S represents the sulfur atom of a cysteine residue C287 as set forth in SEQ ID NO: 1, or cysteine residue C286 as set forth in SEQ ID NO: 2 or 3. CP represents the cereblon polypeptide set forth in SEQ ID NO: 1, 2, or 3, thereby tying the Formula (I*) adduct to a cereblon polypeptide and specific cysteine residue context.
The disclosure also includes related variants and sub-forms such as Formula (Ia) and Formula (Ib), extensive substituent scope for R2 through R18, and stereoisomer and isotopically labeled compound guidance, including deuterium and radioisotopes. The partial content further describes chemical structures and synthetic examples for substituted acrylamide/enone and heteroaryl-piperidine ether compounds, including pyridazin-3-yl oxy and related heteroaryl oxy patterns.
Claims Coverage
The claim coverage centers on a structurally variable Formula (I*) small molecule adduct framework, coupled to a specified cereblon polypeptide context via a sulfur attachment to cysteine residue C287 or C286. In total, the claims present 3 inventive features.
Small molecule adduct of formula (I*)
A small molecule adduct of Formula (I*), or a pharmaceutically acceptable salt or solvate thereof, defined by structural variables A, B, D, E, F, X, Y, L, Z1, multiple R-group definitions, and parameters m, n, and p.
Anchored sulfur attachment to cysteine residues
S represents the sulfur atom of a cysteine residue C287 as set forth in SEQ ID NO: 1, or cysteine residue C286 as set forth in SEQ ID NO: 2 or 3.
Cereblon polypeptide defined by seq ids
CP represents the cereblon polypeptide set forth in SEQ ID NO: 1, 2, or 3.
Claim coverage is anchored on the Formula (I*) small molecule adduct with optional salt or solvate forms, broad substituent definitions, and explicit cysteine residue attachment and cereblon polypeptide definitions.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Cereblon ligandable cysteine profiling in a cereblon-profiling context using protein-probe interactions and proteomics mass spectrometry workflows including LC-MS.
Use across multiple cell types for profiling cereblon ligand-cysteine interactions.
CRBN C287 inhibition assay results are documented, including % inhibition and IC50 values for multiple numbered compounds, with assay notes for inactive compounds.
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