ABSTRACT
Covalent modulation of protein function can have multiple utilities including therapeutics, and probes to interrogate biology. While this field is still viewed with scepticism due to the potential for (idiosyncratic) toxicities, significant strides have been made in terms of understanding how to tune electrophilicity to selectively target specific residues. Progress has also been made in harnessing the potential of covalent binders to uncover novel biology and to provide an enhanced utility as payloads for Antibody Drug Conjugates. This perspective covers the tenets and applications of covalent binders.
Subject(s)
Drug Discovery , Proteins/chemistry , Aminoglycosides/chemistry , Aminoglycosides/metabolism , Benzodiazepines/chemistry , Benzodiazepines/metabolism , Camptothecin/chemistry , Camptothecin/metabolism , Indoles/chemistry , Indoles/metabolism , Molecular Dynamics Simulation , Protein Binding , Proteins/metabolism , Pyrans/chemistry , Pyrans/metabolism , Pyrroles/chemistry , Pyrroles/metabolismABSTRACT
We have identified the pyrazolo[3,4-d]pyrimidine A-420983 (compound 7) as a potent inhibitor of lck. A-420983 exhibits oral efficacy in animal models of delayed-type hypersensitivity and organ transplant rejection.
Subject(s)
Graft Rejection/drug therapy , Immunosuppressive Agents/chemical synthesis , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/antagonists & inhibitors , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Administration, Oral , Animals , Dogs , Heart Transplantation/adverse effects , Humans , Hypersensitivity, Delayed/drug therapy , Immunosuppressive Agents/pharmacokinetics , Immunosuppressive Agents/therapeutic use , Inhibitory Concentration 50 , Interleukin-2/biosynthesis , Mice , Mice, Inbred C57BL , Microsomes, Liver , Models, Animal , Models, Molecular , Molecular Structure , Pyrazoles/administration & dosage , Pyrazoles/pharmacokinetics , Pyrimidines/administration & dosage , Pyrimidines/pharmacokinetics , Structure-Activity RelationshipABSTRACT
A series of para-substituted 3-phenyl pyrazolopyrimidines was synthesized and evaluated as inhibitors of lck. The nature of the substitution affected enzyme selectivity and potency for lck, src, kdr, and tie-2. The para-phenoxyphenyl analogue 2 is an orally active lck inhibitor with a bioavailability of 69% and exhibits an extended duration of action in animal models of T cell inhibition.