7196 research outputs found
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Promise and challenge of β-lactone electrophiles to target Asp12 of mutant KRASG12D
No full textAfter decades of drug discovery research on KRAS inhibitors with the potential to achieve a transformative cancer treatment for some of the most prevalent cancer types, there is still an unmet need to identify KRASG12D mutant selective inhibitors. The early clinical success of a covalent targeting strategy for KRASG12C inhibition prompts further expansion of the concept to target non-cysteine oncogenic mutation sites as in KRASG12D. This endeavor was hampered by the lack of suitable electrophiles for selective, covalent engagement of aspartate. Thanks to the recent discovery of b-lactone-bearing covalent inhibitors of KRASG12D new opportunities for drug discovery are emerging. Based on structural insights from X-ray crystallography and quantum mechanical considerations, we herein describe our work on elucidation of structure-activity and structure-stability correlations to further advance such electrophiles for drug discovery. Guided by predictions of transition state barrier heights for attack of aspartate 12 at the β-lactone electrophile as well as by structure-based design, we generated substituted b-lactones with the aim to achieve a balance of specific reactivity, chemical and metabolic stability. Our optimization strategy was driven by MS-based and cellular covalent target occupancy assays and PD marker analysis, as well as proteome-wide profiling and synthetic chemistry. With an improved understanding of structure and reactivity in biological systems, we wish to expand the use of β-lactones as chemoselective electrophiles and catalyze further applications of covalent carboxylate targeting in medicinal chemistry and drug discovery
Interview on Formulation and Process Development latest trends
No full textN/A
Interview in Q&A format
Online Report on Formulation published by European Pharmaceutical Revie
Navigating IVDR challenges for pharmacokinetic, anti-drug antibodies, andbiomarker assays in early clinical research: a recommendation from the EuropeanBioanalysis Forum
No full textThe European Bioanalysis Forum has observed increasing misclassification of pharmacokinetic, anti-drug antibody, and biomarker research assays not used for patient management under the EuropeanUnion’s In Vitro Diagnostic Regulation, despite their non-diagnostic intent in early clinical development.This misinterpretation, fueled by ambiguous protocol language, limited cross-functional awareness, andinconsistent national implementation, is leading to unnecessary delays in clinical trials and increasedand non-added value regulatory burden. Through a structured evaluation involving a focus workshopand regional roadshows, the European Bioanalysis Forum identified some manageable origins of theissue and its operational consequences. This recommendation paper outlines these observations andwants to propose a pragmatic path forward. This includes clearer regulatory guidance to exemptnoncommercial, non-diagnostic assays from In Vitro Diagnostic Regulation when not developed orintended as registered diagnostics. We also highlight the importance of stakeholder education andcoordinated regulatory dialogue. These steps aim to preserve the regulator’s intent of patient protec-tion while enabling timely and efficient clinical research
Strategies to reduce the use of NHP in development of oncology ADCs with cytotoxic payloads
No full textFor the development of biologics and to a lesser extent small molecules, the use of non-human primates (NHP) for the nonclinical development of new drug candidates can be necessary to assess the potential safety risks in humans. As part of a collaborative effort through IQ DruSafe, a consortium of pharmaceutical companies is actively exploring ways to apply the 3Rs principles (Replacement, Refinement and Reduction) and reduce NHP use in nonclinical drug development while still ensuring patient safety of new potential therapeutic medicines. As one part of 3 workstreams to reduce NHP use in nonclinical safety testing, an IQ DruSafe Working Group (WG) conducted a survey on the use of NHP in toxicology studies used to develop antibody drug conjugates (ADCs) with cytotoxic payloads for the treatment of cancer. The objective of the survey was to understand whether a Good Laboratory Practice (GLP) compliant 3-month NHP study provides impactful additional safety information for ADCs with cytotoxic payloads relative to the 1-month GLP NHP or relative to the 3-month GLP rodent study (when conducted). The goal is to provide supporting evidence for potentially eliminating the 3-month NHP study if the data from the 3-month rodent study or 1-month NHP study is considered sufficient to inform potential safety risk in patients being administered ADCs with cytotoxic payloads. Questions from the survey included whether a 3-month NHP study was conducted and if so, were the results similar or not to those of the 3-month rodent study or the 1-month NHP study, if the toxicities observed were consistent with the expected toxicities of the ADC payload, and questions to address the translatability of the nonclinical findings to that observed in the clinic. In addition, survey questions addressed study design elements particularly related to the number of animals used on studies. The survey results indicated the following key points: for programs with 3-month studies in NHP and rodent, the target organ toxicities were generally similar between the studies and were translatable to humans; for programs with 3-month studies in NHP only, the target organ toxicities were generally similar between the 3-month and 1-month NHP studies and were translatable to humans. Target organ toxicities in both NHP and rodents were mostly attributed to the payload. Overall, survey results indicate an opportunity to reduce NHP use in the development of ADCs with cytotoxic payloads in oncology
Quantum descriptor-based machine-learning modelling of thermal hazard of cyclic sulfamidates
No full textCyclic sulfamidates are commonly used chiral building blocks in organic synthesis. Correct classification of their thermal criticality is crucial for the safe use of these compounds in process development and scale-up. In this study, building on our earlier work,1 we focused on modelling the reaction enthalpy of a family of 5-membered cyclic sulfamidates towards strong bases. The key challenge for the modelling task was the sparse availability of measured reaction enthalpies, with only 29 measurements available. To address this challenge, we used descriptors based on the quantum-chemical properties of the molecules, as they are more closely related to reaction enthalpies than typical cheminformatics-based descriptors. This approach allowed us to avoid relying solely on data-to-fit models, and to focus instead on modelling reaction enthalpies using chemistry-aware techniques, which are more appropriate for small data sets. Three models were constructed using the quantum-chemical descriptors: the first one combining Partial Least Squares (PLS) regression with a Genetic Algorithm (GA), the second one based on the Least Absolute Shrinkage and Selection Operator (LASSO) method and lastly a Gaussian Process Regression (GPR) model. The three models achieved coefficients of determination of 0.78, 0.67 and 0.74, respectively. Although the absolute prediction error values were close to 100 J/g, it is noteworthy that all three techniques provided similar results and accurately classified nearly all compounds into their respective thermal criticality classes. This highlights the methodology's effectiveness in providing a reliable framework for preliminary safety assessment and decision-making in process development
Sulfinyl Aziridines as Stereoselective Covalent Destabilizing Degraders of the Oncogenic Transcription Factor MYC
No full textWhile MYC is a significant oncogenic transcription factor driver of cancer, directly targeting MYC has remained
challenging due to its intrinsic disorder and poorly defined structure, deeming it “undruggable.” Whether
transient pockets formed within intrinsically disordered and unstructured regions of proteins can be selectively
targeted with small molecules remains an outstanding challenge. Here, we developed a bespoke
stereochemically-paired spirocyclic oxindole aziridine covalent library and screened this library for degradation
of MYC. Through this screen, we identified a hit covalent ligand KL2-236, bearing a unique sulfinyl aziridine
warhead, that engaged MYC in vitro as pure MYC/MAX protein complex and in situ in cancer cells to
destabilize MYC, inhibit MYC transcriptional activity and degrade MYC in a proteasome-dependent manner
through targeting intrinsically disordered C203 and D205 residues. Notably, this reactivity was most
pronounced for specific stereoisomers of KL2-236 with a diastereomer KL4-019 that was largely inactive.
Mutagenesis of both C203 and D205 completely attenuated KL2-236-mediated MYC degradation. We have
also optimized our initial KL2-236 hit compound to generate a more durable MYC degrader KL4-219A in
cancer cells. Our results reveal a novel ligandable site within MYC and indicate that certain intrinsically
disordered regions within high-value protein targets, such as MYC, can be interrogated by isomerically unique
chiral small molecules, leading to destabilization and degradation
Guided Sample Pooling in Human Mass Balance Studies: A Recommended Strategic Decision Framework.
No full textRadiolabeled human mass balance studies are crucial for identifying circulating metabolites and understanding drug absorption, excretion, and clearance pathways. Metabolite profiling involves quantifying all drug-related entities, including parent drug and metabolites in plasma and excreta, using extended liquid chromatography methods coupled with detection through scintillation counting, accelerator mass spectrometry, or non-radiolabeled approaches. Given the labor-intensive nature of sample extraction and analysis, we propose a new paradigm that maximizes gathering information through sample pooling strategies. Our proposal introduces sample pooling strategies by integrating both individual and pooled sample schemes, simplifying decisions, and consolidating existing knowledge into a cohesive document. This aligns with the low statistical power typically associated with mass balance studies that dose six to eight subjects. In metabolite profiling, it is common practice to pool samples either from the limited number of subjects participating in a human mass balance study or from different time points of sample collection. This approach improves efficiency while preserving data integrity. Pooling reduces resource constraints and enables the concentration of samples with relatively low radioactivity levels, resulting in higher quality metabolite profiles. Nevertheless, there are situations when analyzing samples from individual subjects or time points may be preferred. This proposal presents guidance and decision trees designed to facilitate informed decisions about sample pooling to maximize data quality of metabolite profiling in human mass balance studies while efficiently managing resources. These recommendations stem from discussions within the mass balance working group of the IQ Consortium
Clinical practice guidelines for the management of basal cell carcinoma in Gorlin syndrome.
No full textGorlin syndrome (GS) is a rare genetic disorder characterized by a predisposition to developing numerous basal cell carcinomas (BCCs) throughout life. The absence of specific clinical guidelines for managing BCCs in GS has resulted in fragmented care and inconsistent treatment approaches.To develop evidence-based guidelines for managing BCCs in GS, addressing both clinical and psychosocial challenges.A multidisciplinary panel employed a modified Grading of Recommendations Assessment, Development and Evaluation approach, integrating systematic reviews, expert surveys, patient interviews, and Delphi consensus rounds to formulate recommendations.The final guidelines include 47 recommendations spanning topical therapies, systemic treatments, surgical interventions, and multimodal strategies. Additional recommendations emphasize shared decision-making, comprehensive monitoring, and psychosocial support to address the chronic nature of BCCs in GS. Specific therapies, including hedgehog inhibitors and field treatments, are recommended to reduce surgical fatigue and enhance quality of life.Given the scarcity of GS-specific data, expert consensus informed several recommendations, highlighting the need for ongoing research to strengthen the evidence base.These guidelines provide a structured framework for improving BCC management in GS, thereby enhancing clinical outcomes and patient quality of life. This process serves as a model for creating patient-centered guidelines in rare conditions with limited evidence
Complex nitrosamine consortium - donation for 2025
No full text3-(isoquinolin-4-yl)-1-nitroso-2-oxoimidazolidine-4-carbonitrile, nitrosamine related to an intermediate in EGT710 (which is no longer continued) is proposed for the yearly nitrosamine donation. Details can be found in the attached ppt
A Mild Rhodium-Catalyzed Asymmetric 1,4-Conjugate Addition of Organoboranes to α-Substituted Heterocyclic Acrylates for Use in Pharmaceutical Products
No full textCyclic acrylates are an under-explored class of electrophile for conjugate addition reactions with aromatic boronic acids. In order to supply a range of saturated heterocycles for medicinal chemistry hit optimization, plate-based parallel screening enabled the discovery of a rhodium-catalyzed 1,4-conjugate addition using Hayashi ligand. Scope exploration included variation in the cyclic acrylate ring size (pyrrolidine, piperidine, azepane), the choice of N-protection group (CBz, Boc, and other carbamates) and the range of boronic acid nucleophiles, amongst other parameters. The influence of these parameters on yield and enantioselectivity is described. The step was then established into a 3-step sequence consisting of: asymmetric conjugate addition; base-mediated epimerization to the trans diastereoisomer; and borohydride reduction of the ester to the alcohol building block. Multi-gram deliveries of complex sp3-rich enantio- and diastereo-meric building blocks could thereby be established