Amgen (India)

Targeted protein degradation via "hijacking" of the ubiquitin-proteasome system using proteolysis targeting chimeras (PROTACs) has evolved into a novel therapeutic modality. The design of PROTACs is challenging; multiple steps involved in PROTAC-induced degradation make it difficult to establish coherent structure-activity relationships. Herein, we characterize PROTAC-mediated ternary complex formation and degradation by employing von Hippel-Lindau protein (VHL) recruiting PROTACs for two different target proteins, SMARCA2 and BRD4. Ternary-complex attributes and degradation activity parameters are evaluated by varying components of the PROTAC's architecture. Ternary complex binding affinity and cooperativity correlates well with degradation potency and initial rates of degradation. Additionally, we develop a ternary-complex structure modeling workflow to calculate the total buried surface area at the interface, which is in agreement with the measured ternary complex binding affinity. Our findings establish a predictive framework to guide the design of potent degraders.

Covalent inhibition of the KRASG12C oncoprotein has emerged as a promising therapeutic approach for the treatment of nonsmall cell lung cancer (NSCLC). The identification of KRASG12C inhibitors has typically relied on the high-throughput screening (HTS) of libraries of cysteine-reactive small molecules or on the attachment of cysteine-reactive warheads to noncovalent binders of KRAS. Such screening approaches have historically been limited in the size and diversity of molecules that could be effectively screened. DNA-encoded library (DEL) screening has emerged as a promising approach to accelerate the preparation and screening of incredibly large and diverse chemical libraries. Here, we describe the design and synthesis of a covalent DEL to screen ∼16 million compounds against KRASG12C. We additionally describe the hit identification, validation, and structure-based optimization that culminated in the identification of a series of structurally novel, potent, and selective covalent inhibitors of KRASG12C with good pharmacokinetic profiles and promising in vivo pharmacodynamic effects.

in mouse xenografts is well tolerated, displaying a robust and dose-dependent inhibition of symmetric dimethylation of arginine in MTAP-del tumor-xenografts and significant concomitant tumor growth inhibition without any significant effect on MTAP-WT tumor xenografts.

Background Female obesity is frequently associated with suboptimal reproductive outcomes in patients undergoing assisted reproductive technologies (ART). This scoping review evaluated traditional and emerging strategies, protocol modifications, and biomarkers aimed at improving ART outcomes in overweight and obese women. Methods A comprehensive PubMed literature search (January 1, 2015–April 23, 2025) identified studies focusing on overweight and obese women undergoing ART. Studies evaluating underweight women or paternal obesity were excluded. Results A total of 50 studies (33 observational and 17 randomized controlled trials) were included. The impact of weight loss interventions was evaluated in 14 studies. Weight loss ≥10% or >5 kg or that achieved after bariatric surgery was associated with improved ART outcomes. Adjunct therapies (N=5) such as micronutrient supplementation (e.g., folate, vitamin B12) demonstrated potential benefits with respect to ovulation, pregnancy, and live birth rates. While overweight or obese women required higher gonadotropin dosages and longer stimulation cycles (N=10), weight loss was associated with decreased gonadotropin consumption and improved ART outcomes. The use of letrozole (N=6), alone or in combination with other stimulation protocols, appeared to increase live birth rates and reduce the risk of miscarriages. Finally, biomarker analyses (N=15) suggested that lipid profiles, reproductive hormones, and inflammatory markers may serve as predictors of ART outcomes. Conclusion Interventions achieving greater degrees of weight loss, adjunct therapies, and letrozole-based protocols may improve ART outcomes, including pregnancy and live birth rates, in overweight and obese women. Personalized treatment protocols, biomarkers, and multidisciplinary approaches are essential for optimizing ART success in this population.

Purpose of Review: Attention-Deficit/Hyperactivity Disorder (ADHD) is increasingly recognised as a lifelong neurodevelopmental condition that persists into adulthood, often associated with significant functional impairment and high psychiatric comorbidity. Despite global advances, services in India remain severely underdeveloped. This paper reviews international guidelines—including those from NICE, the Canadian ADHD Resource Alliance (CADDRA), the British Association for Psychopharmacology (BAP), and the Indian Psychiatric Society (IPS)—to identify best practices for the assessment and multimodal treatment of adult ADHD. Collection and Analysis of Data: The paper reviews international guidelines on adult ADHD care, highlighting convergent recommendations and their applicability to the Indian context. It analyses systemic gaps in India’s service delivery, including the shortage of trained mental health professionals, low public and professional awareness, lack of culturally adapted tools and materials, and limited access to pharmacological and psychosocial interventions. As an applied example, the paper presents Amaha’s adult ADHD care model—developed in 2022—as a scalable, evidence-based approach tailored to the Indian ecosystem. The model integrates psychiatrist-led assessments using the DIVA-5 tool, structured psychoeducation, cautious pharmacotherapy, and adjunctive psychotherapy within a digitally enabled care framework prioritising, continuity of care, family engagement, and community support. Conclusions: This review proposes recommendations to strengthen ADHD care infrastructure in India. These include workforce training, public awareness initiatives, development of India-centric resources, telepsychiatry reforms, and integration of ADHD into public policy and insurance schemes. Addressing adult ADHD in India is both a clinical and public health imperative, requiring scalable, multidisciplinary, and context-sensitive solutions.