3 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
Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study
Because
of their increased activity against activating mutants,
first-generation epidermal growth factor receptor (EGFR) kinase inhibitors
have had remarkable success in treating non-small-cell lung cancer
(NSCLC) patients, but acquired resistance, through a secondary mutation
of the gatekeeper residue, means that clinical responses only last
for 8ā14 months. Addressing this unmet medical need requires
agents that can target both of the most common double mutants: T790M/L858R
(TMLR) and T790M/delĀ(746-750) (TMdel). Herein we describe how a noncovalent
double mutant selective lead compound was optimized using a strategy
focused on the structure-guided increase in potency without added
lipophilicity or reduction of three-dimensional character. Following
successive rounds of design and synthesis it was discovered that cis-fluoro
substitution on 4-hydroxy- and 4-methoxypiperidinyl groups provided
synergistic, substantial, and specific potency gain through direct
interaction with the enzyme and/or effects on the proximal ligand
oxygen atom. Further development of the fluorohydroxypiperidine series
resulted in the identification of a pair of diastereomers that showed
50-fold enzyme and cell based selectivity for T790M mutants over wild-type
EGFR (wtEGFR) in vitro and pathway knock-down in an in vivo xenograft
model
Mitigation of Acetylcholine Esterase Activity in the 1,7-Diazacarbazole Series of Inhibitors of Checkpoint Kinase 1
Checkpoint
kinase 1 (ChK1) plays a key role in the DNA damage response, facilitating
cell-cycle arrest to provide sufficient time for lesion repair. This
leads to the hypothesis that inhibition of ChK1 might enhance the
effectiveness of DNA-damaging therapies in the treatment of cancer.
Lead compound <b>1</b> (GNE-783), the prototype of the 1,7-diazacarbazole
class of ChK1 inhibitors, was found to be a highly potent inhibitor
of acetylcholine esterase (AChE) and unsuitable for development. A
campaign of analogue synthesis established SAR delineating ChK1 and
AChE activities and allowing identification of new leads with improved
profiles. In silico docking using a model of AChE permitted rationalization
of the observed SAR. Compounds <b>19</b> (GNE-900) and <b>30</b> (GNE-145) were identified as selective, orally bioavailable
ChK1 inhibitors offering excellent in vitro potency with significantly
reduced AChE activity. In combination with gemcitabine, these compounds
demonstrate an in vivo pharmacodynamic effect and are efficacious
in a mouse p53 mutant xenograft model