Toward the comprehensive systematic enumeration and synthesis of novel kinase inhibitors based on a 4-anilinoquinazoline binding mode.
There are currently eight small-molecule kinase inhibitors approved as cancer treatments, and a significantly larger number of compounds are in the earlier stages of clinical development. Although kinase inhibitors are most commonly developed in a cancer setting, other disease areas have been targeted. The vast majority of reported kinase small-molecule inhibitors contain functionalities that interact with the adenosine triphosphate (ATP) binding site of the kinase. The 4-anilinoquinazolines have previously been reported as potent epidermal growth factor receptor (EGFR) inhibitors, binding at the 'hinge' region of the ATP site. Subsequently, this chemical series has been optimized against a number of different kinases including Src and Aurora B. Here, we detail the computational enumeration of ring systems that have the ability to make comparable interactions to the 4-anilinoquinazoline core. These were prioritized by computational, medicinal, and synthetic chemistry input, and a number of libraries were subsequently synthesized.
Kettle
Jason G
JG
AstraZeneca, Cancer and Infection Discovery, 50S37, Mereside, Alderley Park, Macclesfield SK10 4TG, United Kingdom.
Ward
Richard A
RA
D019295:Computational Biology; D020128:Inhibitory Concentration 50; D009584:Nitrogen / Q000737:chemistry; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011804:Quinolines; D054852:Small Molecule Libraries; D009584:Nitrogen