Hit-to-Lead: Turning Hits into Promising Drug Candidates
This month’s article, authored by a group of researchers from multiple institutions collaborating with the European Federation for Medicinal Chemistry and Chemical Biology (EFMC) (https://doi.org/10.1002/cmdc.202400931), explores the critical transition from initial drug discovery hits to optimized lead compounds, highlighting key challenges and strategies in this pivotal phase of drug development.
The Hit-to-Lead (H2L) stage is a critical phase in drug discovery, where initial hits identified through high-throughput screening, virtual screening, or small molecule/fragment-based approaches undergo systematic refinement to yield lead compounds with improved pharmacological and physicochemical properties. This process marks a key decision-making juncture, ensuring that only the most promising chemical series advance into lead optimization while mitigating liabilities related to potency, selectivity, pharmacokinetics, and toxicity. While these principles have been extensively applied to small molecules, they are equally relevant in peptide drug discovery, where additional challenges—such as proteolytic stability, permeability, and half-life extension—must be addressed. Strategies like backbone modifications, non-natural amino acid incorporation, and macrocyclization help optimize peptide leads, paralleling the rational design approaches used for small molecules.
A fundamental aspect of H2L is the prioritization and selection of chemical matter based on a comprehensive assessment. While potency is an essential parameter, it must be balanced with selectivity to minimize off-target interactions that could lead to adverse effects. Physicochemical properties such as lipophilicity, solubility, metabolic stability, and permeability play a crucial role in drug-likeness and should be optimized early. Excessive lipophilicity often leads to poor metabolic stability, rapid clearance, and off-target binding, whereas low permeability may result in poor bioavailability.
Lead optimization in H2L relies on iterative structure-activity relationship studies to enhance desirable attributes while addressing potential liabilities. Scaffold modifications, bioisosteric replacements, and strategic incorporation of hydrogen bond donors/acceptors help fine-tune potency, selectivity, and PK properties. The application of ligand efficiency and lipophilic ligand efficiency metrics supports the selection of compounds that achieve potency gains without excessive increases in molecular weight or lipophilicity. Computational modeling and AI-driven predictive analytics further enhance the efficiency of H2L by providing insights into molecular behavior, protein-ligand interactions, and potential liabilities before extensive experimental validation.
A crucial consideration in H2L is early pharmacokinetic and pharmacodynamic evaluation, as in vitro potency alone does not guarantee in vivo efficacy. Pharmacokinetic profiling—including metabolic stability, plasma protein binding, permeability, and clearance—identifies compounds with favorable ADME properties. In parallel, early toxicological assessments help identify potential safety concerns before significant resources are invested in lead optimization.
The decision to progress or discontinue a chemical series is a key turning point in the H2L process. If a series fails to achieve an acceptable balance between potency, selectivity, and drug-like properties, it may be prudent to deprioritize it in favor of alternative scaffolds. Advanced analytics, including machine learning-guided predictive modeling, are increasingly utilized to streamline decision-making and reduce risk before committing to extensive medicinal chemistry efforts.
In conclusion, the Hit-to-Lead stage is a data-driven, multidisciplinary process that integrates medicinal chemistry, computational modeling, structural biology, and pharmacology to refine initial hits into viable lead compounds. Researchers can improve the likelihood of success in lead optimization and clinical development by optimizing key parameters such as potency, selectivity, pharmacokinetic properties, and synthetic feasibility.
To provide further insights, the authors have organized a webinar on H2L strategies, where experts will discuss best practices and real-world case studies. You can access the webinar at (https://www.efmc.info/hit-to-lead).
Open access article: https://doi.org/10.1002/cmdc.202400931
The European Federation for Medicinal Chemistry and Chemical Biology (EFMC) Best Practice Initiative: Hit to Lead, J. Quancard, A. Bach, C. Borsari, R. Craft, C. Gnamm, S. M. Guéret, I. V. Hartung, H. F. Koolman, S. Laufer, S. Lepri, J. Messinger, K. Ritter, G. Sbardella, A. Unzue Lopez, M. K. Willwacher, B. Cox, R. J. Young, ChemMedChem 2025, e202400931.
Sepideh Afshar, Ph.D.
Head of Peptide Therapeutics - Senior Director, Genentech
Member, BPF Scientific Advisory Board
linkedin.com/in/sepideh-afshar-bab3824
Read previous editions of the BPF Journal Club series: https://www.boulderpeptide.org/journal-club