Degraders of cyclin-dependent kinase 12 (CDK12) and uses thereof
Inventors
Che, Jianwei • Gray, Nathanael S. • Zhang, Tinghu • JIANG, Baishan • Gao, Yang • Kwiatkowski, Nicholas Paul
Assignees
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Publication Number
US-12662464-B2
Publication Date
2026-06-23
Expiration Date
Abstract
Provided herein are bifunctional compounds with a moiety (e.g., lenalidomide, thalidomide) that is a binder of an E3 ubiquitin ligase (e.g., Cereblon) and another moiety that is a binder of a target protein (e.g., kinase (e.g., CDK (e.g., CDK9 and/or CDK12))) to induce degradation of the target protein CDK9 and/or CDK12. Also provided are pharmaceutical compositions comprising the bifunctional compounds, and methods of treating and/or preventing diseases (e.g., proliferative diseases, such as cancers (e.g., ovarian cancer, breast cancer, or prostate cancer))). Provided also are methods of inducing the degradation of the target protein (e.g., kinase (e.g., CDK (e.g., CDK9 and/or CDK12))), and methods of inducing apoptosis in a cell in a biological sample or subject by administering the bifunctional compound or composition described herein.
Core Innovation
The invention discloses bifunctional compounds of Formula (I), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. The bifunctional compounds link a CDK9- and/or CDK12-binding moiety to an E3 ubiquitin ligase-binding moiety, such as Cereblon or VHL, to promote ubiquitination and proteasomal degradation. The problem being solved is not explicitly described in patent.
Formula (I) includes specified substituent choices for R1, R2, and R3, defined structural features for Ring A, distinct linker architectures for L1 and L2, and a defined D moiety. Disclosed structural variations include stereochemical variants of pyrrolidine and piperidine motifs, alongside varied hydrocarbon linkers containing carbonyl, oxygen, or nitrogen atoms. The disclosure also encompasses pharmaceutical compositions and methods for selectively degrading CDK9 and/or CDK12 with selectivity over other proteins or CDKs.
Claims Coverage
The claims identify one independent claim, claim 1, directed to compounds of Formula (I) and specified forms thereof, comprising four inventive features.
Bifunctional compound of Formula (I) and specified forms
Claim 1 covers a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, that links a CDK9- and/or CDK12-binding moiety to an E3 ubiquitin ligase-binding moiety.
Substituent selections and Ring A
Claim 1 defines selections for R1, R2, and R3, including halogen, acyl, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, cyano, oxygen-containing, nitrogen-containing, and sulfur-containing groups, with Ring A defined by RY selected from —SO2RY1, —P(=O)(RY2)2, or —C(=O)N(RY3)2, with w1 set to 1 and x and y each set to 0 or 1.
Linker architectures for L1 and L2
Claim 1 defines linker L1 as —NRA—, wherein RA is hydrogen, and linker L2 as an unsubstituted C1–24 hydrocarbon chain wherein one or more chain atoms may independently be replaced with —C(=O)—, —O—, or —NRb—, wherein Rb is hydrogen, with defined attachment points and parameter ranges.
D moiety structures and substituents
Claim 1 defines the D moiety by recited formula alternatives and substituent selections, including choices for XA, R1A, R3A, R3′, R4A, R5A, R2′, R4′, and R5′, alongside specified values for m, n, a1, n1, n2, and n3.
The independent claim establishes protection for the genus of Formula (I) bifunctional compounds and specified pharmaceutical forms, defined by variable substituent selections, linker configurations, and D moiety alternatives.
Stated Advantages
The compounds are described as selectively binding and degrading CDK9 and/or CDK12, promoting ubiquitination and proteasomal degradation.
The compounds are described as having selectivity over other proteins or CDKs.
The compounds are proposed for inducing apoptosis and treating or preventing proliferative diseases, including cancers.
The described experiments report antiproliferative effects in T-ALL cells.
Documented Applications
A pharmaceutical composition comprising a compound of claim 1 or a specified form thereof, optionally with a pharmaceutically acceptable excipient, including combination-therapy embodiments, for the prevention or treatment of proliferative diseases, including ovarian, breast, and prostate cancer.
A method of inducing CDK9 and/or CDK12 degradation by contacting a cell, tissue, or biological sample with a therapeutically effective amount of the compound of claim 1 or a specified form thereof.
Treatment or prevention of proliferative diseases, including cancers such as ovarian cancer, breast cancer, and prostate cancer.
Experimental evaluation of antiproliferative effects and CDK12 degrader activity in T-cell acute lymphoblastic leukemia cells.
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