8 research outputs found
Comparative Analysis of Homo sapiens and Mus musculus Cyclin-Dependent Kinase (CDK) Inhibitor Genes P16 (MTSl) and PIS (MTS2)
Cyclin-dependent kinase inhibitors are a growing family of molecules that regulate important transitions in the cell cycle. At least one of these molecules, p16, has been implicated in human tumorigenesis while its close homolog, p15, is induced by cell contact and transforming growth factor-β (TGF-β). To investigate the evolutionary and functional features of p15 and p16, we have isolated mouse (Mus musculus) homologs of each gene. Comparative analysis of these sequences provides evidence that the genes have similar functions in mouse and human. In addition, the comparison suggests that a gene conversion event is part of the evolution of the human p15 and p16 genes
Discovery of Novel, Dual Mechanism ERK Inhibitors by Affinity Selection Screening of an Inactive Kinase
An
affinity-based mass spectrometry screening technology was used
to identify novel binders to both nonphosphorylated and phosphorylated
ERK2. Screening of inactive ERK2 identified a pyrrolidine analogue <b>1</b> that bound to both nonphosphorylated and phosphorylated
ERK2 and inhibited ERK2 kinase activity. Chemical optimization identified
compound <b>4</b> as a novel, potent, and highly selective ERK1,2
inhibitor which not only demonstrated inhibition of phosphorylation
of ERK substrate p90RSK but also demonstrated inhibition of ERK1,2
phosphorylation on the activation loop. X-ray cocrystallography revealed
that upon binding of compound <b>4</b> to ERK2, Tyr34 undergoes
a rotation (flip) along with a shift in the poly-Gly rich loop to
create a new binding pocket into which <b>4</b> can bind. This
new binding mode represents a novel mechanism by which high affinity
ATP-competitive compounds may achieve excellent kinase selectivity
Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors
BackgroundConstitutive activation of ERK1/2 occurs in various cancers, and its reactivation is a well-described resistance mechanism to MAPK inhibitors. ERK inhibitors may overcome the limitations of MAPK inhibitor blockade. The dual mechanism inhibitor SCH772984 has shown promising preclinical activity across various BRAFV600/RAS-mutant cancer cell lines and human cancer xenografts.MethodsWe have developed an orally bioavailable ERK inhibitor, MK-8353; conducted preclinical studies to demonstrate activity, pharmacodynamic endpoints, dosing, and schedule; completed a study in healthy volunteers (P07652); and subsequently performed a phase I clinical trial in patients with advanced solid tumors (MK-8353-001). In the P07652 study, MK-8353 was administered as a single dose in 10- to 400-mg dose cohorts, whereas in the MK-8353-001 study, MK-8353 was administered in 100- to 800-mg dose cohorts orally twice daily. Safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity were analyzed.ResultsMK-8353 exhibited comparable potency with SCH772984 across various preclinical cancer models. Forty-eight patients were enrolled in the P07652 study, and twenty-six patients were enrolled in the MK-8353-001 study. Adverse events included diarrhea (44%), fatigue (40%), nausea (32%), and rash (28%). Dose-limiting toxicity was observed in the 400-mg and 800-mg dose cohorts. Sufficient exposure to MK-8353 was noted that correlated with biological activity in preclinical data. Three of fifteen patients evaluable for treatment response in the MK-8353-001 study had partial response, all with BRAFV600-mutant melanomas.ConclusionMK-8353 was well tolerated up to 400 mg twice daily and exhibited antitumor activity in patients with BRAFV600-mutant melanoma. However, antitumor activity was not particularly correlated with pharmacodynamic parameters.Trial registrationClinicalTrials.gov NCT01358331.FundingMerck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., and NIH (P01 CA168585 and R35 CA197633)
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Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors
Constitutive activation of ERK1/2 occurs in various cancers, and its reactivation is a well-described resistance mechanism to MAPK inhibitors. ERK inhibitors may overcome the limitations of MAPK inhibitor blockade. The dual mechanism inhibitor SCH772984 has shown promising preclinical activity across various BRAFV600/RAS-mutant cancer cell lines and human cancer xenografts. We have developed an orally bioavailable ERK inhibitor, MK-8353; conducted preclinical studies to demonstrate activity, pharmacodynamic endpoints, dosing, and schedule; completed a study in healthy volunteers (P07652); and subsequently performed a phase I clinical trial in patients with advanced solid tumors (MK-8353-001). In the P07652 study, MK-8353 was administered as a single dose in 10- to 400-mg dose cohorts, whereas in the MK-8353-001 study, MK-8353 was administered in 100- to 800-mg dose cohorts orally twice daily. Safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity were analyzed. MK-8353 exhibited comparable potency with SCH772984 across various preclinical cancer models. Forty-eight patients were enrolled in the P07652 study, and twenty-six patients were enrolled in the MK-8353-001 study. Adverse events included diarrhea (44%), fatigue (40%), nausea (32%), and rash (28%). Dose-limiting toxicity was observed in the 400-mg and 800-mg dose cohorts. Sufficient exposure to MK-8353 was noted that correlated with biological activity in preclinical data. Three of fifteen patients evaluable for treatment response in the MK-8353-001 study had partial response, all with BRAFV600-mutant melanomas. MK-8353 was well tolerated up to 400 mg twice daily and exhibited antitumor activity in patients with BRAFV600-mutant melanoma. However, antitumor activity was not particularly correlated with pharmacodynamic parameters. ClinicalTrials.gov NCT01358331. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., and NIH (P01 CA168585 and R35 CA197633)
Structure Guided Discovery of Novel Pan Metallo-β-Lactamase Inhibitors with Improved Gram-Negative Bacterial Cell Penetration
The use of β-lactam (BL) and
β-lactamase
inhibitor
combination to overcome BL antibiotic resistance has been validated
through clinically approved drug products. However, unmet medical
needs still exist for the treatment of infections caused by Gram-negative
(GN) bacteria expressing metallo-β-lactamases. Previously, we
reported our effort to discover pan inhibitors of three main families
in this class: IMP, VIM, and NDM. Herein, we describe our work to
improve the GN coverage spectrum in combination with imipenem and
relebactam. This was achieved through structure- and property-based
optimization to tackle the GN cell penetration and efflux challenges.
A significant discovery was made that inhibition of both VIM alleles,
VIM-1 and VIM-2, is essential for broad GN coverage, especially against
VIM-producing P. aeruginosa. In addition, pharmacokinetics
and nonclinical safety profiles were investigated for select compounds.
Key findings from this drug discovery campaign laid the foundation
for further lead optimization toward identification of preclinical
candidates
Structure Guided Discovery of Novel Pan Metallo-β-Lactamase Inhibitors with Improved Gram-Negative Bacterial Cell Penetration
The use of β-lactam (BL) and
β-lactamase
inhibitor
combination to overcome BL antibiotic resistance has been validated
through clinically approved drug products. However, unmet medical
needs still exist for the treatment of infections caused by Gram-negative
(GN) bacteria expressing metallo-β-lactamases. Previously, we
reported our effort to discover pan inhibitors of three main families
in this class: IMP, VIM, and NDM. Herein, we describe our work to
improve the GN coverage spectrum in combination with imipenem and
relebactam. This was achieved through structure- and property-based
optimization to tackle the GN cell penetration and efflux challenges.
A significant discovery was made that inhibition of both VIM alleles,
VIM-1 and VIM-2, is essential for broad GN coverage, especially against
VIM-producing P. aeruginosa. In addition, pharmacokinetics
and nonclinical safety profiles were investigated for select compounds.
Key findings from this drug discovery campaign laid the foundation
for further lead optimization toward identification of preclinical
candidates
MK-8353: Discovery of an Orally Bioavailable Dual Mechanism ERK Inhibitor for Oncology
The
emergence and evolution of new immunological cancer therapies has
sparked a rapidly growing interest in discovering novel pathways to
treat cancer. Toward this aim, a novel series of pyrrolidine derivatives
(compound <b>5</b>) were identified as potent inhibitors of
ERK1/2 with excellent kinase selectivity and dual mechanism of action
but suffered from poor pharmacokinetics (PK). The challenge of PK
was overcome by the discovery of a novel 3(<i>S</i>)-thiomethyl
pyrrolidine analog <b>7</b>. Lead optimization through focused
structure–activity relationship led to the discovery of a clinical
candidate <b>MK-8353</b> suitable for twice daily oral dosing
as a potential new cancer therapeutic