Structure-based design, synthesis and characterization of the first irreversible inhibitor of Focal Adhesion Kinase

Focal Adhesion Kinase signaling pathway and its functions have been involved in the development and aggressiveness of tumor malignancy, it then presents a promising cancer therapeutic target. Several reversible FAK inhibitors have been developed and are being conducted in clinical trials. On the other hand, irreversible covalent inhibitors would bring many desirable pharmacological features including high potency and increased duration of action. Herein we report the structure-guided development of the first highly potent and irreversible inhibitor of the FAK kinase. This inhibitor showed a very potent decrease of autophosphorylation of FAK in squamous cell carcinoma. A cocrystal structure of the FAK kinase domain in complex with this compound revealed the inhibitor binding mode within the ATP binding site and confirmed the covalent linkage between the targeted Cys427 of the protein and the inhibitor

Syntheses and anti-HIV and human cluster of differentiation 4 (CD4) down-modulating potencies of pyridine-fused cyclotriazadisulfonamide (CADA) compounds.

CADA compounds selectively down-modulate human cell-surface CD4 protein and are of interest as HIV entry inhibitors and as drugs for asthma, rheumatoid arthritis, diabetes and some cancers. Postulating that fusing a pyridine ring bearing hydrophobic substituents into the macrocyclic scaffold of CADA compounds may lead to potent compounds with improved properties, 17 macrocycles were synthesized, 14 with 12-membered rings having an isobutylene head group, two arenesulfonyl side arms, and fused pyridine rings bearing a para substituent. The analogs display a wide range of CD4 down-modulating and anti-HIV potencies, including some with greater potency than CADA, proving that a highly basic nitrogen atom in the 12-membered ring is not required for potency and that hydrophobic substituents enhance potency of pyridine-fused CADA compounds. Cytotoxicities of the new compounds compared favorably with those of CADA, showing that incorporation of a pyridine ring into the macrocyclic scaffold can produce selective compounds for potently down-modulating proteins of medicinal interest.status: publishe