DOT1L degraders and uses thereof
Inventors
Assignees
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Publication Number
US-12331069-B2
Publication Date
2025-06-17
Expiration Date
Abstract
Provided herein are bifunctional compounds with a moiety or domain that is a binder of the ubiquitin receptor RPN13 and another moiety or domain that is a binder of a target protein DOT1L to induce degradation of DOT1L. Also provided are pharmaceutical compositions comprising the bifunctional compounds, and methods of treating and/or preventing diseases (e.g., proliferative diseases, such as cancers). Provided also are methods of inducing the degradation of DOT1L by administering a bifunctional compound or composition described herein, wherein one domain of the bifunctional compound is a binder of the ubiquitin receptor RPN13 and another domain of the compound is a binder of the target protein DOT1L in a subject.
Core Innovation
The invention relates to bifunctional compounds of Formula (I) and pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. The compounds bind DOT1L and a ubiquitin receptor RPN13 (ADRM1), and recruit DOT1L to the proteasome to induce DOT1L degradation. The disclosure defines a linker L that connects a DOT1L-binding moiety A to a moiety D, together with ring B and substituent parameters.
The moiety D is defined by formulas IA or IB and includes phenyl, naphthyl, monocyclic heteroaryl, and bicyclic heteroaryl groups, optionally substituted with multiple functional groups. The structure further specifies X as —CH2— or —O— and constrains n1, n2, n3, g, and g1 within stated ranges. The disclosure also defines substitution options for R8, R9, R10, R11, and R12, and additional variables Y, Z, R7, K, p, and q.
The core structural innovation is the combination of the DOT1L-binding moiety and the defined RPN13-binding moiety D through the chemically defined divalent linker L with attachment points lR and lA. The linker L includes substituted or unsubstituted C1–50 hydrocarbon chains with permitted heteroatom replacements, functional moieties, and cyclic units. Representative compounds and degradation readouts are described for DOT1L degraders such as dDOT1L-6, dDOT1L-7, and dDOT1L-8.
Claims Coverage
The consolidated claims coverage identifies two independent structural themes: a Formula (I) compound scaffold with defined moieties and a bifunctional compound that connects DOT1L-binding and RPN13-binding elements. The inventive features center on the detailed structure of D, the divalent linker L, ring B, and the constrained substituent variables.
Formula (I) compound scaffold with defined D moiety
A compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer, wherein D is of formula IA or IB and is defined with phenyl, naphthyl, monocyclic heteroaryl, or bicyclic heteroaryl options, together with the specified variable framework for Y, Z, R1/R2, p, and q.
Defined divalent linker L with attachment points lR and lA
A compound of Formula (I) wherein L is a divalent moiety joining the point of attachment lR to D and the point of attachment lA to the moiety of formula (I), with permitted substituted or unsubstituted C1–50 hydrocarbon chains, heteroatom replacements, cyclic units, and other specified linker substructures.
Bifunctional DOT1L and RPN13-binding compound
A compound of Formula (I) in which the linker L connects a DOT1L-binding moiety A and a moiety D associated with RPN13/ADRM1 binding, with X as —CH2— or —O—, ring B as an optionally substituted 5-10 membered heterocyclyl or optionally substituted 5-14 membered heteroaryl group, and defined ranges for n1, n2, n3, g, and g1.
Substitution constraints for R8 to R12 and additional variables
A compound of Formula (I) wherein R8, R9, and R10 are hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group; R11 is halogen, optionally substituted acyl, or optionally substituted alkyl; each R12 is independently hydrogen, optionally substituted acyl, or an oxygen protecting group; and Y, Z, R7, K, p, and q are defined by the stated options.
The claims collectively cover a structurally defined Formula (I) compound and a bifunctional DOT1L/RPN13-binding compound, each with explicit linker, ring, and substitution constraints.
Stated Advantages
Selective, RPN13-mediated proteolysis directed to DOT1L degradation versus other methyltransferases.
Induces DOT1L degradation by recruiting DOT1L to the proteasome.
Documented Applications
Inducing degradation of DOT1L in a subject by administering a therapeutically effective amount of a compound of Formula (I) or a specified pharmaceutically acceptable form.
Inducing DOT1L degradation in biological samples [procedural detail omitted for safety].
Use in assays/schematics with Western blot and cell-growth readouts showing DOT1L degradation, including H3K79me2 readouts, for DOT1L degraders such as dDOT1L-6, dDOT1L-7, and dDOT1L-8 with a RA190 control.
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