14 research outputs found
Pyridones as Highly Selective, Noncovalent Inhibitors of T790M Double Mutants of EGFR
The rapid advancement of a series
of noncovalent inhibitors of
T790M mutants of EGFR is discussed. The optimization of pyridone <b>1</b>, a nonselective high-throughput screening hit, to potent
molecules with high levels of selectivity over wtEGFR and the broader
kinome is described herein
Discovery of a Noncovalent, Mutant-Selective Epidermal Growth Factor Receptor Inhibitor
Inhibitors
targeting the activating mutants of the epidermal growth
factor receptor (EGFR) have found success in the treatment of EGFR
mutant positive non-small-cell lung cancer. A secondary point mutation
(T790M) in the inhibitor binding site has been linked to the acquired
resistance against those first generation therapeutics. Herein, we
describe the lead optimization of a series of reversible, pan-mutant
(L858R, del<sub>746–750,</sub> T790M/L858R, and T790M/del<sub>746–750</sub>) EGFR inhibitors. By use of a noncovalent double
mutant (T790M/L858R and T790M/del<sub>746–750</sub>) selective
EGFR inhibitor (<b>2</b>) as a starting point, activities against
the single mutants (L858R and del<sub>746–750</sub>) were introduced
through a series of structure-guided modifications. The in vitro ADME-PK
properties of the lead molecules were further optimized through a
number of rational structural changes. The resulting inhibitor (<b>21</b>) exhibited excellent cellular activity against both the
single and double mutants of EGFR, demonstrating target engagement
in vivo and ADME-PK properties that are suitable for further evaluation.
The reversible, noncovalent inhibitors described complement the covalent
pan-mutant EGFR inhibitors that have shown encouraging results in
recent clinical trials
Discovery of 7‑Tetrahydropyran-2-yl Chromans: β‑Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors That Reduce Amyloid β‑Protein (Aβ) in the Central Nervous System
In an attempt to increase selectivity
vs Cathepsin D (CatD) in
our BACE1 program, a series of 1,3,4,4a,10,10a-hexahydropyranoÂ[4,3-b]Âchromene
analogues was developed. Three different Asp-binding moieties were
examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines
in order to modulate potency, selectivity, efflux, and permeability.
Using structure-based design, substitutions to improve binding to
both the S3 and S2′ sites of BACE1 were explored. An acyl guanidine
moiety provided the most potent analogues. These compounds demonstrated
10–420 fold selectivity for BACE1 vs CatD, and were highly
potent in a cell assay measuring Aβ<sub>1–40</sub> production
(5–99 nM). They also suffered from high efflux. Despite this
undesirable property, two of the acyl guanidines achieved free brain
concentrations (C<sub>free,brain</sub>) in a guinea pig PD model sufficient
to cover their cell IC<sub>50</sub>s. Moreover, a significant reduction
of Aβ<sub>1–40</sub> in guinea pig, rat, and cyno CSF
(58%, 53%, and 63%, respectively) was observed for compound <b>62</b>
Cell Active Hydroxylactam Inhibitors of Human Lactate Dehydrogenase with Oral Bioavailability in Mice
A series
of trisubstituted hydroxylactams was identified as potent
enzymatic and cellular inhibitors of human lactate dehydrogenase A.
Utilizing structure-based design and physical property optimization,
multiple inhibitors were discovered with <10 ÎĽM lactate IC<sub>50</sub> in a MiaPaca2 cell line. Optimization of the series led
to <b>29</b>, a potent cell active molecule (MiaPaca2 IC<sub>50</sub> = 0.67 ÎĽM) that also possessed good exposure when
dosed orally to mice
Discovery of a Potent and Selective BCL‑X<sub>L</sub> Inhibitor with <i>in Vivo</i> Activity
A-1155463, a highly potent and selective
BCL-X<sub>L</sub> inhibitor,
was discovered through nuclear magnetic resonance (NMR) fragment screening
and structure-based design. This compound is substantially more potent
against BCL-X<sub>L</sub>-dependent cell lines relative to our recently
reported inhibitor, WEHI-539, while possessing none of its inherent
pharmaceutical liabilities. A-1155463 caused a mechanism-based and
reversible thrombocytopenia in mice and inhibited H146 small cell
lung cancer xenograft tumor growth <i>in vivo</i> following
multiple doses. A-1155463 thus represents an excellent tool molecule
for studying BCL-X<sub>L</sub> biology as well as a productive lead
structure for further optimization