5 research outputs found
Structure-Based Design of GNE-495, a Potent and Selective MAP4K4 Inhibitor with Efficacy in Retinal Angiogenesis
Diverse
biological roles for mitogen-activated protein kinase kinase
kinase kinase 4 (MAP4K4) have necessitated the identification of potent
inhibitors in order to study its function in various disease contexts.
In particular, compounds that can be used to carry out such studies
in vivo would be critical for elucidating the potential for therapeutic
intervention. A structure-based design effort coupled with property-guided
optimization directed at minimizing the ability of the inhibitors
to cross into the CNS led to an advanced compound <b>13</b> (GNE-495)
that showed excellent potency and good PK and was used to demonstrate
in vivo efficacy in a retinal angiogenesis model recapitulating effects
that were observed in the inducible <i>Map4k4</i> knockout
mice
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
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 8–14 months. Addressing this unmet medical need requires
agents that can target both of the most common double mutants: T790M/L858R
(TMLR) and T790M/del(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