Discovery of the Potent and Selective ATR Inhibitor Camonsertib (RP-3500).

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. Preclinical evaluation focused on the impact of camonsertib on myelosuppression, and an exploration of intermittent dosing schedules to allow recovery of the erythroid compartment and mitigate anemia. Camonsertib is currently undergoing clinical evaluation both as a single agent and in combination with talazoparib, olaparib, niraparib, lunresertib, or gemcitabine (NCT04497116, NCT04972110, NCT04855656). A preliminary recommended phase 2 dose for monotherapy was identified as 160 mg QD given 3 days/week.

Identification of RP-6685, an Orally Bioavailable Compound that Inhibits the DNA Polymerase Activity of Polθ.

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 of human Polθ (encoded by POLQ). A high-throughput screening campaign of 350,000 compounds identified an 11 micromolar hit, giving rise to the N2-substituted fused pyrazolo series, which was validated by biophysical methods. Structure-based drug design efforts along with optimization of cellular potency and ADME ultimately led to the identification of RP-6685: a potent, selective, and orally bioavailable Polθ inhibitor that showed in vivo efficacy in an HCT116 BRCA2-/- mouse tumor xenograft model.

Discovery of an Orally Bioavailable and Selective PKMYT1 Inhibitor, RP-6306.

PKMYT1 is a regulator of CDK1 phosphorylation and is a compelling therapeutic target for the treatment of certain types of DNA damage response cancers due to its established synthetic lethal relationship with CCNE1 amplification. To date, no selective inhibitors have been reported for this kinase that would allow for investigation of the pharmacological role of PKMYT1. To address this need compound 1 was identified as a weak PKMYT1 inhibitor. Introduction of a dimethylphenol increased potency on PKMYT1. These dimethylphenol analogs were found to exist as atropisomers that could be separated and profiled as single enantiomers. Structure-based drug design enabled optimization of cell-based potency. Parallel optimization of ADME properties led to the identification of potent and selective inhibitors of PKMYT1. RP-6306 inhibits CCNE1-amplified tumor cell growth in several preclinical xenograft models. The first-in-class clinical candidate RP-6306 is currently being evaluated in Phase 1 clinical trials for treatment of various solid tumors.

CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition.

Amplification 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 therapies1-4. 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. To inhibit PKMYT1, we developed RP-6306, an orally bioavailable and selective inhibitor that shows single-agent activity and durable tumour regressions when combined with gemcitabine in models of CCNE1 amplification. RP-6306 treatment causes unscheduled activation of CDK1 selectively in CCNE1-overexpressing cells, promoting early mitosis in cells undergoing DNA synthesis. CCNE1 overexpression disrupts CDK1 homeostasis at least in part through an early activation of the MMB-FOXM1 mitotic transcriptional program. We conclude that PKMYT1 inhibition is a promising therapeutic strategy for CCNE1-amplified cancers.

RP-3500: A Novel, Potent, and Selective ATR Inhibitor that is Effective in Preclinical Models as a Monotherapy and in Combination with PARP Inhibitors.

Ataxia telangiectasia and Rad3-related (ATR) kinase protects genome integrity during DNA replication. RP-3500 is a novel, orally bioavailable clinical-stage ATR kinase inhibitor (NCT04497116). RP-3500 is highly potent with IC50 values of 1.0 and 0.33 nmol/L in biochemical and cell-based assays, respectively. RP-3500 is highly selective for ATR with 30-fold selectivity over mammalian target of rapamycin (mTOR) and more than 2,000-fold selectivity over ataxia telangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK), and phosphatidylinositol 3-kinase alpha (PI3Kα) kinases. In vivo, RP-3500 treatment results in potent single-agent efficacy and/or tumor regression in multiple xenograft models at minimum effective doses (MED) of 5 to 7 mg/kg once daily. Pharmacodynamic assessments validate target engagement, with dose-proportional tumor inhibition of phosphorylated checkpoint kinase 1 (pCHK1) (IC80 = 18.6 nmol/L) and induction of phosphorylated H2A.X variant histone (γH2AX), phosphorylated DNA-PK catalytic subunit (pDNA-PKcs), and phosphorylated KRAB-associated protein 1 (pKAP1). RP-3500 exposure at MED indicates that circulating free plasma levels above the in vivo tumor IC80 for 10 to 12 hours are sufficient for efficacy on a continuous schedule. However, short-duration intermittent (weekly 3 days on/4 days off) dosing schedules as monotherapy or given concomitantly with reduced doses of olaparib or niraparib, maximize tumor growth inhibition while minimizing the impact on red blood cell depletion, emphasizing the reversible nature of erythroid toxicity with RP-3500 and demonstrating superior efficacy compared with sequential treatment. These results provide a strong preclinical rationale to support ongoing clinical investigation of the novel ATR inhibitor, RP-3500, on an intermittent schedule as a monotherapy and in combination with PARP inhibitors as a potential means of maximizing clinical benefit.

Changing relationships: how does patient involvement transform professional identity? An ethnographic study.

OBJECTIVES: To understand identity tensions experienced by health professionals when patient partners join a quality improvement committee. DESIGN: Qualitative ethnographic study based on participatory observation. SETTING: An interdisciplinary quality improvement committee of a Canadian urban academic family medicine clinic with little previous experience in patient partnership. PARTICIPANTS: Two patient partners, seven health professionals (two family physicians, two residents, one pharmacist, one nurse clinician and one nurse practitioner) and three members of the administrative team. DATA COLLECTION: Data collection included compiled participatory observations, logbook notes and semi-structured interviews, collected between the summer of 2017 to the summer of 2019. DATA ANALYSIS: Ghadiri's identity threats theoretical framework was used to analyse qualitative material and to develop conceptualising categories, using QDA Miner software (V.5.0). RESULTS: All professionals with a clinical care role and patient partners (n=9) accepted to participate in the ethnographic study and semi-structured interviews (RR=100%). Transforming the 'caregiver-patient' relationship into a 'colleague-colleague' relationship generated identity upheavals among professionals. Identity tensions included competing ideals of the 'good professional', challenges to the impermeability of the patient and professional categories, the interweaving of symbols associated with one or the other of these identities, and the inner balance between the roles of caregiver and colleague. CONCLUSION: This research provides a new perspective on understanding how working in partnership with patients transform health professionals' identity. When they are called to work with patients outside of a simple therapeutic relationship, health professionals may feel tensions between their identity as caregivers and their identity as colleague. This allows us to better understand some underlying tensions elicited by the arrival of different patient engagement initiatives (eg, professionals' resistance to working with patients, patients' status and remuneration, professionals' concerns toward patient 'representativeness'). Partnership with patients imply the construction of a new relational framework, flexible and dynamic, that takes into account this coexistence of identities.

[Mental health in primary care: applying psychiatric knowledge to primary care or a whole different practice?] / Les médecins de famille et la santé mentale : une expertise en mal de reconnaissance ou une pratique différente de celle des psychiatres ?

BACKGROUND: In Canada and several other countries, large cohorts of patients who used to be followed in psychiatric clinics are now steered toward primary care. To support this new reality, measures have been taken and investments made in service organization, collaborative work arrangements, and teaching geared toward primary care clinicians. However, these initiatives were implemented when little was known about GPs' needs. METHODS: Using a qualitative approach, we analyzed the content of GPs' statements to explore when, why, and for what concerns GPs are inclined to collaborate with or seek advice from psychiatrists. RESULTS: The results provide an innovative understanding of their practice and its boundaries and suggest that the management of patients with mental health problems in primary care is actually very different from what is done in psychiatry. CONCLUSION: Uncertainty about the broad spectrum of what is normal, the longitudinal aspect of the relationship, and the proximity of the soma are among the specificities we found that could be helpful in organizing care and educating primary care clinicians and medical students more coherently and efficiently.

The 'mad scientists': psychoanalysis, dream and virtual reality.

The author explores the concept of reality-testing as a means of assessing the relationship with reality that prevails in dream and in virtual reality. Based on a model developed by Jean Laplanche, she compares these activities in detail in order to determine their respective independence from the function of reality-testing. By carefully examining the concept of hallucination in the writings of Freud and Daniel Dennett, the author seeks to pinpoint the specific modalities of interaction between perceptions, ideas, wishes and actions that converge in the 'belief' and in the 'sense of reality'. The paper's main thesis consists of the distinction that it draws between immediacy-testing and reality-testing, with the further argument that this distinction not only dissipates the conceptual vagueness that generally surrounds the latter of the two concepts but also that it promotes a more precise analysis of the function of reality in dream and in virtual reality.