Methods for designing inhibitors of serine/threonine kinases and tyrosine kinases
AssigneeVertex Pharmaceuticals Incorporated
InventorsMichael Shin-San Su, Ted Fox, Keith Philip Wilson, Ursula A. Germann
Life of this patent
Estimating the term…
Abstract
The invention relates to methods for designing inhibitors of serine/threonine kinases and tyrosine kinases, particularly MAP kinases, through the use of ATP-binding site mutants of those kinases. The methods of this invention take advantage of the fact that the mutant kinases are capable of binding inhibitory compounds of other kinases with greater affinity than the corresponding wild-type kinase. The invention further relates to the mutant kinases themselves and crystallizable co-complexes of the mutant kinase and the inhibitory compound.
Claims17
A method for designing an inhibitor of a second serine/threonine kinase or a second tyrosine kinase comprising the steps of:
- a. identifying amino acids in an ATP binding site of a first serine/threonine kinase or a first tyrosine kinase which form close contacts with a compound bound to said ATP binding site;
- b. employing protein alignment means to identify a second serine/threonine kinase or a second tyrosine kinase that form some, but not all, of the close contacts formed between said compound and said first serine/threonine kinase or said first tyrosine kinase;
- c. altering an amino acid in the ATP binding site of said second serine/threonine kinase or said second tyrosine kinase to create a mutant second serine/threonine kinase or a mutant second tyrosine kinase, wherein said compound binds with at least 10-fold greater affinity to said mutant second kinase than to said second kinase;
- d. confirming that said compound binds with greater affinity to said mutant second serine/threonine kinase or said mutant second tyrosine kinase than to said second serine/threonine kinase or said second tyrosine kinase;
- and
- e. using molecular modeling means to modify said compound to create an inhibitor of said second kinase, such that said inhibitor binds to said second kinase with at least 10-fold greater affinity than said compound binds to said second kinase.
A mutant second serine/threonine kinase or tyrosine kinase characterized by:
- a. at least one amino acid substitution in an ATP binding site as compared to a corresponding naturally occurring second kinase;
- b. the ability to bind with a Ki or a Kd of less than 10 μM a compound that binds to an ATP binding site of a first serine/threonine kinase or tyrosine kinase;
- and
- c. the ability to bind said compound with at least a 10-fold lower Ki or Kd than the Ki or Kd for said compound with said second kinase.
Dependencies are inferred from the claim text.