Hemiasterlin derivatives for conjugation and therapy
Inventors
Kline, Toni • Yin, Qun • Bajjuri, Krishna
Assignees
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Publication Number
US-11866515-B2
Publication Date
2024-01-09
Expiration Date
Abstract
Provided herein are hemiasterlin derivatives, conjugates thereof, compositions comprising the derivatives or conjugates thereof, methods of producing the derivatives and conjugates thereof, and methods of using the derivatives, conjugates, and compositions for the treatment of cell proliferation. The derivatives, conjugates, and compositions are useful in methods of treatment and prevention of cell proliferation and cancer, methods of detection of cell proliferation and cancer, and methods of diagnosis of cell proliferation and cancer. In an embodiment, the hemiasterlin derivatives are according to Formula 1000: or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein Ar, L, W1, W4, W5, SG, and R are as described herein.
Core Innovation
The disclosed invention relates to compound scaffolds defined by Formula 1000 and related formulas, including pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer forms. The structure includes an aromatic portion Ar, a linkage portion L that is absent or CH2, and defined placeholder positions for X, R, W1 through W5, EG, each RT, and HP, with multiple structural positions stated as absent and SG as a single bond.
The disclosure also includes conjugate compound embodiments and scaffold variants tied to formulas C1 through C13b, E1, F1 through F13b, G1 through G13b, and I through XVIb, together with example scaffold drawings and attachment points. The scaffold definitions further include release trigger group RT, eliminator group EG, and hydrophilic group HP functionality, with RT, HP, and SG described in relation to conjugation architecture and hydrophilicity.
The disclosure also describes bioorthogonal conjugation and releasing chemistry, including alkyne-azide cycloaddition, inverse-demand Diels-Alder tetrazine/strained-alkene ligation, thiol/disulfide-forming reactions, thiol-maleimide linkage formation, and carbonyl-oxyamine oxime linkage. Conjugates are produced by contacting compounds bearing terminal conjugating groups with a second electrophile partner selected from azide, alkyne, tetrazine, strained-alkene, thiol, maleimide, carbonyl, or oxyamine, and releasing reactions are described as cleaving to active moieties.
Claims Coverage
The consolidated claim coverage centers on one independent claim for a Formula 1000 compound and its pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer, with multiple structural constraints on Ar, L, X, R, and the absence of W1 through W5, EG, each RT, and HP while SG is a single bond. Dependent claims refine Ar, specify L as CH2, and add pharmaceutical composition coverage and formula-based embodiments.
Formula 1000 compound scaffold with constrained Ar and absent substituents
A compound according to Formula 1000, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein Ar is a divalent monocyclic aryl or heteroaryl, or a divalent fused bicyclic aryl or heteroaryl within the recited ring-size limits; L is absent or CH2; X is defined as recited; R is hydrogen; and W1, W2, W3, W4, W5, EG, each RT, and HP are all absent while SG is a single bond.
Ar selection to monocyclic heteroaryl
The compound of Formula 1000 where Ar is a substituted or unsubstituted divalent five- or six-membered monocyclic heteroaryl group.
Ar selection to fused bicyclic aryl or heteroaryl
The compound of Formula 1000 where Ar is a divalent fused bicyclic aryl or a divalent eight-, nine-, or ten-membered substituted or unsubstituted fused bicyclic heteroaryl group.
L specifically CH2
The compound of Formula 1000 where L is specifically CH2.
Pharmaceutical composition with excipient, carrier, or diluent
A pharmaceutical composition comprising the Formula 1000 compound, or a pharmaceutically acceptable salt or tautomer thereof, together with a pharmaceutically acceptable excipient, carrier, or diluent.
Embodiments defined by formulas (1) through (8)
The Formula 1000 compound, or a pharmaceutically acceptable salt or tautomer thereof, according to any of the provided chemical formulas (1) through (8).
Overall, the claims focus on a tightly constrained Formula 1000 scaffold defined by specific Ar ring classes, L restricted to absent or CH2, and multiple placeholder positions required to be absent while SG is a single bond. The dependent claims further narrow Ar, fix L to CH2, and extend the scope to pharmaceutical compositions and embodiments according to formulas (1) through (8).
Stated Advantages
Inhibition of tubulin polymerization.
Inhibition of cell proliferation.
Addresses poor pGP substrate properties of hemiasterlin.
Selective reaction and low cross-reactivity with biomolecule functional groups.
Documented Applications
Therapeutic and/or diagnostic uses for cell proliferation and cancer.
Therapeutic and prophylactic uses associated with tubulin polymerization inhibition and cell proliferation, including cancer treatment contexts.
Methods of inhibiting tubulin polymerization.
Conjugates and methods of producing conjugates using reactants with bioorthogonal handles.
Pharmaceutical compositions containing the claimed compound with pharmaceutically acceptable excipients, carriers, or diluents.
Assay methods including concepts described as translation reaction and luciferase assay, ELISA, and gel staining (Coomassie/silver stained gel).
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