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-11771689-B2
Publication Date
2023-10-03
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 invention relates to a small molecule adduct having a structure of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. The structure is defined by structural positions A, B, D, E, X, Y, and L, with extensive substituent definitions for multiple variable groups and index parameters m, n, p, and q. The disclosure also defines related Formula (I*), Formula (Ib), Formula I, Formula II, Formula III, and Formula IV, and includes example compound embodiments shown in images.
The structure is explicitly anchored by a sulfur atom S that 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, and by CP representing the cereblon polypeptide set forth in SEQ ID NO: 1, 2, or 3. The disclosed adducts are described in a cereblon (CRBN) context and as covalent modification of cereblon cysteine residues, including an adduct formed between a cereblon cysteine residue and the reactive compound.
The document further provides variable substituent rules, including selections for X, Y, and L, and extensive substitution patterns for R groups such as halogen, CN, carbonyl-containing groups, ether linkages, and polyether linker options. It also includes contextual discussion of the ubiquitin-proteasome system and the CRL4CRBN complex (CUL4-RBX1-DDB1-CRBN), and references CRBN C287 engagement assay results and sample-preparation proteomics context.
Claims Coverage
The consolidated claim coverage centers on clm-00001. One independent claim is present across the inputs, directed to a small molecule adduct of Formula (Ia), optionally as a pharmaceutically acceptable salt or solvate, with extensive structural variability and explicit cereblon cysteine residue context. The inventive features merge the repeated claim elements into a single Formula (Ia) scaffold with specified substituent positions, index constraints, and SEQ ID-defined S and CP definitions.
Formula (Ia) small molecule adduct scaffold
A small molecule adduct having a structure of Formula (Ia), including a pharmaceutically acceptable salt or solvate thereof, with defined A, B, D, E, X, Y, and L positions and extensive variable definitions for substituents including R2, R3, R4, R5, R6, R8, R10, R11, R12, R13, R14, R15, R16, R17, and R18, together with index constraints m, n, p, and q.
Cysteine residue and cereblon polypeptide anchoring
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, and CP represents the cereblon polypeptide set forth in SEQ ID NO: 1, 2, or 3.
Defined substituent selections for positions X, Y, and L
X is absent, —O—, —NR6—, or —S—; Y is H, halogen, —OR6, or substituted or unsubstituted C1–C6 alkyl or substituted or unsubstituted C1–C6 haloalkyl; and L is —C(=O)—, —S(=O)—, or —S(=O)2—.
Variable substituent system and index constraints
The claim set further includes variable substituent rules for R13 and other R groups, including polyether linker options, and numerical constraints on m, n, p, and q.
Overall, the claim coverage is directed to clm-00001, a Formula (Ia) small molecule adduct with optional pharmaceutically acceptable salts or solvates, extensive substituent variability, and explicit attachment context defined by cereblon cysteine residues C287 or C286 and cereblon polypeptide SEQ ID numbers.
Stated Advantages
Not explicitly described in patent.
Documented Applications
CRBN C287 inhibition assay results are documented, including percent inhibition at 500 μM and IC50 values for cereblon (CRBN) C287 engagement.
Cereblon protein sequence/identity for cereblon variants is documented using SEQ ID NOs 1-5.
A referenced sample-prep proteomics protocol is included in the document context, associated with proteomics-related assay/sample preparation.
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