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Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic…
TLDR
This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity, which was found to be potent against wild-type ALK and clinically reported ALK kinase domain mutations.
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Physiochemical drug properties associated with in vivo toxicological outcomes.
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Potent and selective nonpeptidic inhibitors of procollagen C-proteinase.
TLDR
Sulfonamide 56 (UK-421,045) was selected as a candidate for further preclinical evaluation as a topically applied, dermal anti-scarring agent and demonstrates excellent selectivity over MMPs involved in wound healing (>10 000-fold).
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Design of potent and selective inhibitors to overcome clinical anaplastic lymphoma kinase mutations resistant to crizotinib.
TLDR
The successful application of both structure-based and lipophilic-efficiency-focused drug design resulted in aminopyridine 8e, which was potent across a broad panel of engineered ALK mutant cell lines and showed suitable preclinical pharmacokinetics and robust tumor growth inhibition in a crizotinib-resistant cell line (H3122-L1196M).
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4-methylpteridinones as orally active and selective PI3K/mTOR dual inhibitors.
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Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04979064 through Structure-Based Drug Design.
TLDR
The lead optimization for the tricyclic series improved the in vitro potency and addressed a number of ADMET issues including high metabolic clearance mediated by both P450 and aldehyde oxidase (AO), poor permeability, and poor solubility.
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Discovery of (10R)-7-Amino-12-Fluoro-2,10,16-Trimethyl-15-Oxo-10,15,16,17-Tetrahydro-2H-8,4-(Metheno)Pyrazolo[4,3-H][2,5,11]Benzoxadiazacyclotetradecine-3-Carbonitrile (Pf-06463922), a Macrocyclic…
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Discovery of the highly potent PI3K/mTOR dual inhibitor PF-04691502 through structure based drug design
The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays crucial roles in cell growth, proliferation and survival. Genomic aberrations in the PI3K pathway, such as mutational activation of…
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Discovery of 1-{(3R,4R)-3-[({5-Chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)methyl]-4-methoxypyrrolidin-1-yl}prop-2-en-1-one (PF-06459988), a Potent, WT Sparing,…
TLDR
PF-06459988 was discovered as a novel, third generation irreversible inhibitor, which demonstrates high potency and specificity to the T790M-containing double mutant EGFRs, minimal intrinsic chemical reactivity of the electrophilic warhead, and greatly reduced proteome reactivity relative to earlier irreversible EGFR inhibitors.
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Discovery of novel, potent, and selective inhibitors of 3-phosphoinositide-dependent kinase (PDK1).
TLDR
The optimized analogues have a PDK1 Ki of 1 nM and >100-fold selectivity against PI3K/AKT-pathway kinases and ADME properties were improved by lowering the lipophilicity with heteroatom replacements in the saturated, five-membered ring.
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