Discovery of a Novel Class of Exquisitely Selective Mesenchymal-Epithelial Transition Factor (c-MET) Protein Kinase Inhibitors and Identification of the Clinical Candidate 2‑(4-(1-(Quinolin-6-ylmethyl)‑1<i>H</i>‑[1,2,3]triazolo[4,5‑<i>b</i>]pyrazin-6-yl)‑1<i>H</i>‑pyrazol-1-yl)ethanol (PF-04217903) for the Treatment of Cancer

The c-MET receptor tyrosine kinase is an attractive oncology target because of its critical role in human oncogenesis and tumor progression. An oxindole hydrazide hit <b>6</b> was identified during a c-MET HTS campaign and subsequently demonstrated to have an unusual degree of selectivity against a broad array of other kinases. The cocrystal structure of the related oxindole hydrazide c-MET inhibitor <b>10</b> with a nonphosphorylated c-MET kinase domain revealed a unique binding mode associated with the exquisite selectivity profile. The chemically labile oxindole hydrazide scaffold was replaced with a chemically and metabolically stable triazolopyrazine scaffold using structure based drug design. Medicinal chemistry lead optimization produced 2-(4-(1-(quinolin-6-ylmethyl)-1<i>H</i>-[1,2,3]­triazolo­[4,5-<i>b</i>]­pyrazin-6-yl)-1<i>H</i>-pyrazol-1-yl)­ethanol (<b>2</b>, <b>PF-04217903</b>), an extremely potent and exquisitely selective c-MET inhibitor. <b>2</b> demonstrated effective tumor growth inhibition in c-MET dependent tumor models with good oral PK properties and an acceptable safety profile in preclinical studies. <b>2</b> progressed to clinical evaluation in a Phase I oncology setting

Discovery of <i>N</i>‑((3<i>R</i>,4<i>R</i>)‑4-Fluoro-1-(6-((3-methoxy-1-methyl‑1<i>H</i>‑pyrazol-4-yl)amino)-9-methyl‑9<i>H</i>‑purin-2-yl)pyrrolidine-3-yl)acrylamide (PF-06747775) through Structure-Based Drug Design: A High Affinity Irreversible Inhibitor Targeting Oncogenic EGFR Mutants with Selectivity over Wild-Type EGFR

Mutant epidermal growth factor receptor (EGFR) is a major driver of non-small-cell lung cancer (NSCLC). Marketed first generation inhibitors, such as erlotinib, effect a transient beneficial response in EGFR mutant NSCLC patients before resistance mechanisms render these inhibitors ineffective. Secondary oncogenic EGFR mutations account for approximately 50% of relapses, the most common being the gatekeeper T790M substitution that renders existing therapies ineffective. The discovery of PF-06459988 (<b>1</b>), an irreversible pyrrolopyrimidine inhibitor of EGFR T790M mutants, was recently disclosed. Herein, we describe our continued efforts to achieve potency across EGFR oncogenic mutations and improved kinome selectivity, resulting in the discovery of clinical candidate PF-06747775 (<b>21</b>), which provides potent EGFR activity against the four common mutants (exon 19 deletion (Del), L858R, and double mutants T790M/L858R and T790M/Del), selectivity over wild-type EGFR, and desirable ADME properties. Compound <b>21</b> is currently being evaluated in phase-I clinical trials of mutant EGFR driven NSCLC

Discovery of 1‑{(3<i>R</i>,4<i>R</i>)‑3-[({5-Chloro-2-[(1-methyl‑1<i>H</i>‑pyrazol-4-yl)amino]‑7<i>H</i>‑pyrrolo[2,3‑<i>d</i>]pyrimidin-4-yl}oxy)methyl]-4-methoxypyrrolidin-1-yl}prop-2-en-1-one (PF-06459988), a Potent, WT Sparing, Irreversible Inhibitor of T790M-Containing EGFR Mutants

First generation EGFR TKIs (gefitinib, erlotinib) provide significant clinical benefit for NSCLC cancer patients with oncogenic EGFR mutations. Ultimately, these patients’ disease progresses, often driven by a second-site mutation in the EGFR kinase domain (T790M). Another liability of the first generation drugs is severe adverse events driven by inhibition of WT EGFR. As such, our goal was to develop a highly potent irreversible inhibitor with the largest selectivity ratio between the drug-resistant double mutants (L858R/T790M, Del/T790M) and WT EGFR. A unique approach to develop covalent inhibitors, optimization of <i>reversible binding affinity</i>, served as a cornerstone of this effort. PF-06459988 was discovered as a novel, third generation irreversible inhibitor, which demonstrates (i) high potency and specificity to the T790M-containing double mutant EGFRs, (ii) minimal intrinsic chemical reactivity of the electrophilic warhead, (iii) greatly reduced proteome reactivity relative to earlier irreversible EGFR inhibitors, and (iv) minimal activity against WT EGFR