Identification of small-molecule candidate therapeutics capable of inhibiting or interfering with a target protein-protein interaction
AssigneeIsis Innovation Limited
InventorsTerence Rabbitts, Tomoyuki Tanaka
Life of this patent
Estimating the term…
Abstract
The present invention provides a method of screening method small-molecule candidate therapeutics capable of inhibiting or interfering with intracellular protein-protein interactions, such as cancer associated oncogenic protein interactions and in particular RAS and LMO2 protein-protein interactions. The present invention also provides methods and assays for rationalized drug design based on identifying small molecular weight protein-protein interaction inhibitor molecules that emulate antibody therapeutics products.
Claims15
A method of identifying a small-molecule candidate therapeutic capable of inhibiting or interfering with a target protein-protein interaction, the method comprising:
- (i) identifying a high affinity intracellular single variable domain or antibody fragment that is associated with a protein-protein interaction, blockade of which has an effect on a disease or has an adverse biological effect;
- (ii) determining contact residues involved in the protein-protein interaction between target protein and the high affinity intracellular single variable domain or antibody fragment;
- (iii) engineering a derivative of the high affinity intracellular single variable domain that has a de-matured affinity for binding to the target as compared with the starting variable domain;
- (iv) contacting the engineered de-matured lower binding affinity intracellular single variable domain with small-molecule candidate therapeutics and;
- (v) determining binding partner(s) of the de-matured lower binding affinity intracellular single variable domain so as to identify candidate therapeutic(s).
A method of screening a small-molecule chemical library using at least one de-matured single domain for identifying small-molecule emulators of an antibody fragment binding site wherein the de-matured molecule has a binding affinity in the range of mM to μM.
A method of screening a small-molecule chemical library using at least one de-matured single domain for identifying small-molecule emulators of an antibody fragment binding site wherein the de-matured molecule has a binding affinity in the range of millimolar to micromolar.
A binding assay for identifying inhibitors of RAS protein-protein interactions, the assay comprising a de-matured anti-RAS single domain target and an activated RAS-GTP form.
Dependencies are inferred from the claim text.