Publications by authors named "M J Zinda"
ATR is a key kinase in the DNA-damage response (DDR) that is synthetic lethal with several other DDR proteins, making it an attractive target for the treatment of genetically selected solid tumors. Herein we describe the discovery of a novel ATR inhibitor guided by a pharmacophore model to position a key hydrogen bond. Optimization was driven by potency and selectivity over the related kinase mTOR, resulting in the identification of camonsertib (RP-3500) with high potency and excellent ADME properties.
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- Predictive biomarkers are important for guiding targeted cancer treatments, and the ATR inhibitor camonsertib shows promise for tumors with specific DNA damage response gene alterations.
- In a phase 1 trial involving 120 patients with advanced solid tumors, camonsertib demonstrated good tolerance, with the most common side effect being anemia.
- Preliminary results showed a recommended phase 2 dose of 160 mg weekly, with some patients experiencing clinical and molecular responses, particularly those with ovarian cancer and specific genetic alterations.
Article Synopsis
- Patient selection for cancer therapy can be enhanced by analyzing gene-specific loss of heterozygosity (LOH) and biallelic loss of function (LOF) in tumors.* -
- The report introduces SNiPDx, a targeted next-generation sequencing panel that successfully detects LOH and biallelic LOF in 26 key genes related to DNA damage response from formalin-fixed, paraffin-embedded (FFPE) tumor samples.* -
- SNiPDx shows high sensitivity (95%) and specificity (91%) in detecting these genetic alterations, accurately identifying ATM mutations and LOH events, making it a promising tool for precision diagnostics in cancer treatment.*
Combinations of ataxia telangiectasia- and Rad3-related kinase inhibitors (ATRis) and poly(ADP-ribose) polymerase inhibitors (PARPis) synergistically kill tumor cells through modulation of complementary DNA repair pathways, but their tolerability is limited by hematological toxicities. To address this, we performed a genome-wide CRISPR-Cas9 screen to identify genetic alterations that hypersensitize cells to a combination of the ATRi RP-3500 with PARPi, including deficiency in RNase H2, RAD51 paralog mutations, or the "alternative lengthening of telomeres" telomere maintenance mechanism. We show that RP-3500 and PARPi combinations kill cells carrying these genetic alterations at doses sub-therapeutic as single agents.
View Article and Find Full Text PDFAmplification of the CCNE1 locus on chromosome 19q12 is prevalent in multiple tumour types, particularly in high-grade serous ovarian cancer, uterine tumours and gastro-oesophageal cancers, where high cyclin E levels are associated with genome instability, whole-genome doubling and resistance to cytotoxic and targeted therapies. To uncover therapeutic targets for tumours with CCNE1 amplification, we undertook genome-scale CRISPR-Cas9-based synthetic lethality screens in cellular models of CCNE1 amplification. Here we report that increasing CCNE1 dosage engenders a vulnerability to the inhibition of the PKMYT1 kinase, a negative regulator of CDK1.
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