4 research outputs found
5-Bromo-3-(indan-1-yloxy)pyridin-2-amine
The title compound, C14H13BrN2O, was obtained by reaction of indan-1-yl methanesulfonate with 2-amino-5-bromopyridin-3-ol in the presence of caesium carbonate. The indane ring system is approximately planar [all but one of the C atoms are coplanar within 0.03 Å, the latter atom being displaced by 0.206 (2) Å from the mean plane through the remaining atoms] and forms a dihedral angle of 58.41 (4)° with the pyridine ring. In the crystal, centrosymmetrically related molecules are linked into dimers by N—H⋯N hydrogen bonds
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