Conjugates of CC-1065 analogs and bifunctional linkers
Inventors
Beusker, Patrick Henry • Coumans, Rudy Gerardus Elisabeth • Elgersma, Ronald Christiaan • Menge, Wiro Michael Petrus Bernardus • Joosten, Johannes Albertus Frederikus • Spijker, Henri Johannes • De Groot, Franciscus Marinus Hendrikus
Assignees
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Publication Number
US-11052155-B2
Publication Date
2021-07-06
Expiration Date
Abstract
This invention relates to novel analogs of the DNA-alkylating agent CC-1065 and to their conjugates. Furthermore this invention concerns intermediates for the preparation of said agents and conjugates. The conjugates are designed to release their (multiple) payload after one or more activation steps and/or at a rate and time span controlled by the conjugate in order to selectively deliver and/or controllably release one or more of said DNA alkylating agents. The agents, conjugates, and intermediates can be used to treat an illness that is characterized by undesired (cell) proliferation. As an example, the agents and the conjugates of this invention may be used to treat a tumor.
Core Innovation
The invention relates to compounds of formula (IV) or pharmaceutically acceptable salts thereof, in which a reactive moiety RM is linked, optionally via a linking group L, to one or more V1 moieties. Each V1 is independently absent or a conditionally-cleavable or conditionally-transformable moiety that can be cleaved or transformed by a chemical, photochemical, physical, biological, or enzymatic process. Each V1 is connected to a self-eliminating spacer system Y comprised of one or more self-elimination ω-amino aminocarbonyl cyclization spacers.
Each Y is linked to V1, optionally L, and one or more Z, where p is a positive integer representing a degree of branching and z is a positive integer equal to or smaller than the total number of attachment sites for Z. Each Z is independently a compound of formula (I), (II), (I′), or (II′), and DB is a DNA-binding moiety selected within the defined structures. The Z portion includes R1 as a leaving group and broadly defined substituent positions, with optional substitution by formula (V) through Y′ connections.
The disclosed embodiments include multiple DB structural families, including DB1 to DB9, with defined leaving-group and substituent patterns, and include selected structural variants and isomeric or mixture embodiments. The description also includes reactive-moiety activation patterns, including halide and hydroxy leaving groups and active ester options such as mesyloxy, triflyloxy, and tosyloxy, together with examples of peptide-like V1 motifs such as valylcitrulline, valyllysine, phenylalanyllysine, alanylphenylalanyllysine, and D-alanylphenylalanyllysine.
Claims Coverage
The claims center on one independent formula (IV) scaffold with dependent refinements that narrow reactive-moiety selection, selected structural and isomeric variants, and pharmaceutical composition scope. The inventive features combine RM, optional L, conditionally-cleavable or conditionally-transformable V1, self-eliminating spacer system Y, and branched Z units containing DNA-binding moieties DB.
Compound of formula (IV) with reactive moiety RM and conditionally-cleavable V1 moieties
A compound of formula (IV) or pharmaceutically acceptable salt thereof, wherein RM is a reactive moiety, L is independently absent or a linking group linking RM to one or more V1 and/or Y, and each V1 is independently absent or a conditionally-cleavable or conditionally-transformable moiety cleavable or transformable by a chemical, photochemical, physical, biological, or enzymatic process.
Self-eliminating spacer system Y linked to branching Z substituents
Each Y is a self-eliminating spacer system comprised of one or more self-elimination ω-amino aminocarbonyl cyclization spacers, each Y linked to V1, optionally L, and one or more Z, with p representing a degree of branching and z a positive integer equal to or smaller than the total number of attachment sites for Z.
DNA-binding moiety DB in Z with leaving group R1 and defined substituent classes
Each Z is independently a compound of formula (I), (II), (I′), or (II′), wherein DB is a DNA-binding moiety and R1 is a leaving group, with broadly defined substituent classes and optional substitution by formula (V) through Y′.
Reactive-moiety activation and leaving-group options
The reactive moiety RM includes X35 and X36 selected from specified groups and Rdd selected from specified substituent classes, including active-ester and leaving-group options such as halide, hydroxy, mesyloxy, triflyloxy, and tosyloxy forms.
Isomeric embodiments with selected V1 motifs and substituents
The compound is defined as an isomer or mixture of isomers where R5a is H, methyl, or methoxy, with V1 selected from valylcitrulline, valyllysine, phenylalanyllysine, alanylphenylalanyllysine, or D-alanylphenylalanyllysine, together with selected L, AZ, and CL substituents shown in the figures.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition comprising a compound as specified in claim 1, and a pharmaceutical composition containing a compound according to dependent claim 2, each together with a pharmaceutically acceptable carrier.
The claims are directed to the same formula (IV) scaffold in which RM is connected, optionally through L, to conditionally-cleavable or conditionally-transformable V1 moieties, which are linked through a self-eliminating ω-amino aminocarbonyl cyclization spacer system Y to branched Z units carrying DNA-binding moieties DB. Dependent claims further narrow RM activation and leaving-group patterns, specify selected isomeric and V1 embodiments, and add pharmaceutical composition scope.
Stated Advantages
Improves targeting/therapeutic index via structures that can require two sequential cleavages/transformations to release Z.
Improved solubility and residence time.
Reduced aggregation and immunogenicity.
Attenuation of cytotoxicity if prematurely cleaved.
Increase DNA binding affinity.
Increase water solubility.
Selective delivery and controlled release at tumor sites.
Improved pharmacokinetic properties.
Improved polarity via water-solubilizing group designs.
Reported reductions in relative aggregate amount after conjugation for selected formula (IV) compounds versus a reference (100%), which the document states demonstrate an advantage of cyclization spacers.
Improves solubility, binding affinity, and selectivity.
Reduces aggregation and side effects.
Avoids increased hydrophobicity and aggregation tendency associated with overly fused multi-cyclic aromatic systems.
Mitigates premature conjugate release and cell entry.
Potentially enhances DNA binding via electrostatics.
Provides detoxification via oxidation or hydration of the vinyl double bond.
Documented Applications
Tumor-targeted selective delivery and controlled release at tumor sites.
Therapeutic conjugates and linker-agent conjugates.
Antibody-drug conjugate, HSA conjugates, and multi-enzyme/trigger cleavage contexts mentioned in the document.
Branching spacer-linked drug/biomolecule conjugate structures illustrated using an antibody (Ab).
Conjugate/targeting-moiety formation via a reactive moiety or in situ reaction, with possible albumin binding.
Conjugate release and cell entry mitigation in relation to substituent choices.
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