A5039168292- Advanced Breast Cancer Therapies
- Estrogen and related hormone effects
- PARP inhibition in cancer therapy
- DNA Repair Mechanisms
- Cell death mechanisms and regulation
- Cancer therapeutics and mechanisms
- Microtubule and mitosis dynamics
- Virus-based gene therapy research
- Analytical Methods in Pharmaceuticals
- CRISPR and Genetic Engineering
- Analytical Chemistry and Chromatography
- Chemical synthesis and alkaloids
- Cancer Genomics and Diagnostics
- Pesticide Residue Analysis and Safety
- Cancer-related Molecular Pathways
- Antibiotics Pharmacokinetics and Efficacy
- Inflammatory mediators and NSAID effects
- Protein Kinase Regulation and GTPase Signaling
- Protein Structure and Dynamics
- BRCA gene mutations in cancer
- Pregnancy and Medication Impact
- Metabolomics and Mass Spectrometry Studies
- Adenosine and Purinergic Signaling
- Drug Solubulity and Delivery Systems
- Cholinesterase and Neurodegenerative Diseases
Telesta Therapeutics (Canada)
2021-2024
Hypha Discovery (United Kingdom)
2024
AstraZeneca (United Kingdom)
2013
Merck Canada Inc. (Canada)
2004-2011
TransCanada (Canada)
2007-2010
Merck & Co., Inc., Rahway, NJ, USA (United States)
2009
Concordia University
2003
Amplification of the CCNE1 locus on chromosome 19q12 is prevalent in multiple tumour types, particularly high-grade serous ovarian cancer, uterine tumours and gastro-oesophageal cancers, where high cyclin E levels are associated with genome instability, whole-genome doubling resistance to cytotoxic targeted therapies
Current approaches to discovery-stage drug metabolism studies (pharmacokinetics, microsomal stability, etc. ) typically use triple-quadrupole-based for quantitative analysis. This necessitates the optimization of parameters such as Q1 and Q3 m/z values, collision energy, interface voltages. These detect only specified compound information about other components, metabolites, is lost. The ability perform full-scan acquisition analysis would eliminate need while enabling detection metabolites...
DNA polymerase theta (Polθ) is an attractive synthetic lethal target for drug discovery, predicted to be efficacious against breast and ovarian cancers harboring BRCA-mutant alleles. Here, we describe our hit-to-lead efforts in search of a selective inhibitor human Polθ (encoded by POLQ). A high-throughput screening campaign 350,000 compounds identified 11 micromolar hit, giving rise the N2-substituted fused pyrazolo series, which was validated biophysical methods. Structure-based design...
PKMYT1 is a regulator of CDK1 phosphorylation and compelling therapeutic target for the treatment certain types DNA damage response cancers due to its established synthetic lethal relationship with CCNE1 amplification. To date, no selective inhibitors have been reported this kinase that would allow investigation pharmacological role PKMYT1. address need compound 1 was identified as weak inhibitor. Introduction dimethylphenol increased potency on These analogs were found exist atropisomers...
ATR is a key kinase in the DNA-damage response (DDR) that synthetic lethal with several other DDR proteins, making it an attractive target for treatment of genetically selected solid tumors. Herein we describe discovery novel inhibitor guided by pharmacophore model to position hydrogen bond. Optimization was driven potency and selectivity over related mTOR, resulting identification camonsertib (RP-3500) high excellent ADME properties. Preclinical evaluation focused on impact...
Abstract Endocrine therapies (ET) with cyclin-dependent kinase 4/6 (CDK4/6) inhibition are the standard treatment for estrogen receptor-α-positive (ER+) breast cancer, however drug resistance is common. In this study, proteogenomic analyses of patient-derived xenografts (PDXs) from patients 22 ER+ cancer demonstrated that protein kinase, membrane-associated tyrosine/threonine one (PKMYT1), a WEE1 homolog, estradiol (E2) regulated in E2-dependent PDXs and constitutively expressed when growth...
BRCA1/2 -mutated cancer cells must adapt to the genome instability caused by their deficiency in homologous recombination. Identifying and targeting these adaptive mechanisms may provide new therapeutic strategies. Here we present results of genome-scale CRISPR/Cas9-based synthetic lethality screens isogenic pairs BRCA1- BRCA2-deficient that identified gene encoding CIP2A as essential a wide range BRCA1 - BRCA2 cells. Unlike PARP inhibition, CIP2A-deficiency does not cause accumulation...
Abstract Amplification of the gene encoding cyclin E ( CCNE1 ) is an oncogenic driver in several malignancies and associated with chemoresistance poor prognosis. To uncover therapeutic targets for -amplified tumors, we undertook genome-scale CRISPR/Cas9-based synthetic lethality screens cellular models amplification. Here, report that increasing dosage engenders a vulnerability to inhibition PKMYT1 kinase, negative regulator CDK1. inhibit PKMYT1, developed RP-6306, orally bioavailable...
Camonsertib is a novel ATR kinase inhibitor in clinical development for advanced cancers targeting sensitizing mutations. This article describes the identification and biosynthesis of an <i>N</i>-glucuronide metabolite camonsertib. was first observed human hepatocyte incubations subsequently isolated to determine structure, evaluate its stability as part bioanalytical method use standard estimating concentration phase I samples. The scaled-up using purified bacterial culture preparation...
<div>Abstract<p>Endocrine therapies (ET) with cyclin-dependent kinase 4/6 (CDK4/6) inhibition are the standard treatment for estrogen receptor-α-positive (ER<sup>+</sup>) breast cancer, however drug resistance is common. In this study, proteogenomic analyses of patient-derived xenografts (PDXs) from patients 22 ER<sup>+</sup> cancer demonstrated that protein kinase, membrane-associated tyrosine/threonine one (PKMYT1), a WEE1 homolog, estradiol (E2)...
<p>A model of PKMYT1 gene transcription regulated by ERα and E2F factors</p>
<p>Immunoblotting of MCF7 EDR and Palbo-R cell lines to validate p53 protein knockdown</p>
<p>KIPA-SureQuant in T47D parental and palbociclib-resistant cells</p>
<p>Statistical analyses of data in Figures 6B, 6C, and S3.</p>
<p>WEE1 mRNA levels in relationship to anastrozole and palbociclib response</p>