3 research outputs found
Discovery of a Novel Class of Exquisitely Selective Mesenchymal-Epithelial Transition Factor (c-MET) Protein Kinase Inhibitors and Identification of the Clinical Candidate 2â(4-(1-(Quinolin-6-ylmethyl)â1<i>H</i>â[1,2,3]triazolo[4,5â<i>b</i>]pyrazin-6-yl)â1<i>H</i>âpyrazol-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]ÂtriazoloÂ[4,5-<i>b</i>]Âpyrazin-6-yl)-1<i>H</i>-pyrazol-1-yl)Âethanol
(<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>â((3<i>R</i>,4<i>R</i>)â4-Fluoro-1-(6-((3-methoxy-1-methylâ1<i>H</i>âpyrazol-4-yl)amino)-9-methylâ9<i>H</i>âpurin-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 1â{(3<i>R</i>,4<i>R</i>)â3-[({5-Chloro-2-[(1-methylâ1<i>H</i>âpyrazol-4-yl)amino]â7<i>H</i>âpyrrolo[2,3â<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 patientsâ 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