Targeted therapeutics

Inventors

Jain, Neera • Ying, Weiwen • Chimmanamada, Dinesh U. • Zhang, Junyi • Kale, Amit

Assignees

Madrigal Pharmaceuticals Inc

Abstract

The present invention provides pharmacological compounds including an effector moiety conjugated to a binding moiety that directs the effector moiety to a biological target of interest. Likewise, the present invention provides compositions, kits, and methods (e.g., therapeutic, diagnostic, and imaging) including the compounds. The compounds can be described as a protein interacting binding moiety-drug conjugate (SDC-TRAP) compounds, which include a protein interacting binding moiety and an effector moiety. For example, in certain embodiments directed to treating cancer, the SDC-TRAP can include an Hsp90 inhibitor conjugated to a cytotoxic agent as the effector moiety.

Core Innovation

The invention relates to the SDC-TRAP platform chemistry and therapeutic rationale using Hsp90-binding moieties. It provides binding-molecule scaffolds and Hsp90-binding compounds as targeting components within SDC-TRAP pharmaceutical conjugates, including Hsp90-binding compounds AUY-922, AT-13387, IPI-504, ganetespib, and PI-493.

The disclosed SDC-TRAP constructs comprise a protein-interacting binding moiety and an effector moiety, configured to enter target cells and become trapped intracellularly, enabling selective payload release. The binding moiety interaction and affinity modulate intracellular trapping and timing of effector moiety release, and the document contrasts this approach with untargeted drugs and antibody-drug conjugates.

The disclosure also describes cleavable or enzymatically cleavable linker concepts, optional prodrug strategy for Hsp90 ligands, and prodrug-like embodiments as part of the pharmaceutical conjugate constructions. It further describes target selection principles for therapeutic and imaging molecular target pairs, therapeutic uses connected to Hsp90 and Hsp90 client proteins, anti-inflammatory use via glucocorticoid receptor/client-protein degradation and glucocorticoid ligands, and folate receptor endocytosis with pemetrexed and a folate recognizing fragment.

Claims Coverage

Only one independent claim is present across the provided items. It covers a production process for SDC-TRAP-0063 Sodium (or its tautomer), with four inventive features centered on dissolution in tert-butanol, pH adjustment above about 9.8, serial filtration, and aseptic vial filling followed by lyophilization.

The claim coverage is directed to producing SDC-TRAP-0063 Sodium (or its tautomer) using the specified solvent and pH conditions, filtration through at least two 0.2 µm filters in series, and aseptic vial filling with lyophilization.

Stated Advantages

Documented Applications