Protein–Ligand Crystal Structures Can Guide the Design of Selective Inhibitors of the FGFR Tyrosine Kinase

Abstract

The design of compounds that selectively inhibit a single kinase is a significant challenge, particularly for compounds that bind to the ATP site. We describe here how protein-ligand crystal structure information was able both to rationalize observed selectivity and to guide the design of more selective compounds. Inhibition data from enzyme and cellular screens and the crystal structures of a range of ligands tested during the process of identifying selective inhibitors of FGFR provide a step-by-step illustration of the process. Steric effects were exploited by increasing the size of ligands in specific regions in such a way as to be tolerated in the primary target and not in other related kinases. Kinases are an excellent target class to exploit such approaches because of the conserved fold and small side chain mobility of the active form.

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

“…Understanding the cocrystal structure of the ligand-ATP-binding site of particular kinases may aid the discovery of more selective inhibitors (Norman et al, 2012b). For example, this approach has been used to develop selective inhibitors of FGFR tyrosine kinase (Norman et al, 2012a). Targeting allosteric binding sites that lie outside the highly conserved ATP-binding site offers hope for greater potency and specificity and may also protect against the development of drug resistance by mutation of the ATP-binding site (Wu et al, 2015b).…”

Optimization of Highly Kinase Selective Bis-anilino Pyrimidine PAK1 Inhibitors

“…Selectivity against some key kinase antitargets, KDR and FGFR1, 13 was modest. Since 1 originated from an EphB4 kinase project, 14 a member of the Src kinase family, high activity for Src kinase was expected.…”

FGFR1 Kinase Inhibitors: Close Regioisomers Adopt Divergent Binding Modes and Display Distinct Biophysical Signatures

“…22 The FGFR1-bound conformation of the desmethoxy analog 3 (Figure 2d) is similar to the previous conformation of a close analog having a bromine substituent on the pyrimidine ring in complex with FGFR1 (PDB code: 4F65). 8 In contrast to the structures of FGFR1 in complex with the bromine substituted analog or 1, respectively, the observed electron density did not support the presence of a water molecule at the FGFR1−3 interface. In this structure the plane of the phenyl ring is also perpendicular to the plane of the core.…”

“…Recently, Norman et al reported on the discovery of pyrazolylaminopyrimidines as potent FGFR1 inhibitors and their structure-based optimization that led to the identification of compound 1 ( Figure 1). 8 In our continuing studies aimed at optimizing ligand-binding site interactions, the substitution pattern of the 3,5-dimethoxyphenyl group of 1 was varied. Interestingly, a tight structure−activity relationship was observed: moving one methoxy function from the 5-to the 4-position (compound 2) resulted in a drop of inhibitory potency/binding affinity of almost 2 orders of magnitude ( Figure 1).…”