Drug Hunter's Most Popular Content of 2025 Highlights Industry Trends

Drug Hunter's most-accessed content in 2025 reflected common needs across the drug discovery community for practical tools and insights into emerging trends. The platform's educational resources, scientific reviews, and case studies highlighted key developments in target selection, new modalities, and medicinal chemistry strategies that are reshaping the field.

The most widely used resources included practical PK calculators designed to support day-to-day needs of drug discovery scientists and project teams. The PK calculator suite includes a unit conversion tool to rapidly convert between µM and ng/mL, an animal study requirement calculator to estimate compound material demands for PK, efficacy, or tox studies, and a human equivalent dose estimator to contextualize doses used across preclinical in vivo experiments. Additionally, resources on bioisosteric replacement strategies and basic medicinal chemistry principles, including ligand efficiency, lipophilicity, ionization state, and binding kinetics, were extensively accessed by scientists seeking to optimize solubility, permeability, pharmacokinetics, and selectivity while minimizing off-target effects.

Target selection remained paramount to drug discovery success in 2025. Programs anchored in strong human genetics, clear disease association, and a tractable therapeutic hypothesis were better positioned to translate into clinical benefit. As development timelines lengthen and competitive pressures intensify, careful target selection remains one of the most decisive factors differentiating programs.

Throughout the year, targets traditionally dominated by biologics began to open up to small molecule drug development. This shift was particularly evident in immunology, where new strategies allowed intervention against proteins long considered impossible to drug with small molecules. Transcription factors such as IRF5 and STAT6 emerged as particularly compelling opportunities. Multiple programs advanced efforts to directly inhibit or degrade IRF5, providing the first credible path to oral modulation of a central inflammatory regulator. Kymera's degrader KT-621 advanced with data supporting its potential as an oral alternative to antibody-based IL-4/IL-13 blockade by dupilumab, while direct STAT6 inhibitors also demonstrated biologic-like efficacy in preclinical models.

New modalities continued to redefine what is possible in drug discovery. RIPTACs (regulated induced proximity targeting chimeras) emerged as a pivot in induced-proximity pharmacology, moving beyond protein degradation to disease-context-dependent modulation of protein function. A key milestone came with recent Phase 1/2 data showing the tolerability and efficacy of the first-to-clinic candidate HLD-0915, which led to the $3B buyout of Halda by Johnson & Johnson.

Significant progress occurred in the space of CNS-targeted degraders. By 2025, oral degraders with demonstrated CNS exposure moved from fantasy to reality. Early clinical readouts from Arvinas' oral LRRK2 degrader program positioned degraders as a distinct, disease-modifying approach to the treatment of Parkinson's disease. Although questions regarding potential for lung toxicity remain, recent data suggest clear clinical differentiation from traditional LRRK2 inhibition.

RNA targeting also came to the forefront in 2025. Splicing modulators and other RNA-targeting therapies matured into an established modality. While clinical precedent in SMA laid the foundation, the narrative broadened in 2025, with RNA therapeutics intervening upstream from the synthesis of disease-causing proteins. For splicing modulation specifically, there was growing emphasis on CNS disease and other challenging settings.

The FDA approved 44 new therapies as of late December 2025, compared with 50 in 2024. Among the most-read case studies were recently approved drugs, including the next-generation triple-combination CFTR modulator Alyftrek (vanzacaftor/tezacaftor/deutivacaftor), the first-in-class DPP1 inhibitor Brinsupri (brensocatib), and Cobenfy (xanomeline/trospium chloride), the first schizophrenia treatment with a novel mechanism of action in decades. Several late-stage and emerging clinical programs, including the pan-RAS inhibitor daraxonrasib, the oral IL-23R antagonist icotrokinra, oral GLP-1R agonists orforglipron and naperiglipron, the OX2R agonist alixorexton, the oral PD-L1 macrocycle BMS-986238, and the BTK degrader bexobrutideg, had a significant impact on the 2025 drug discovery landscape.

One of the clearest trends in drug discovery was the rapid rise of oral macrocycles. Five out of the 10 most popular case studies fell into this category. Once considered niche, beyond-Ro5 chemistry evolved into a deliberate and powerful design strategy. Macrocycles are now featured in some of the most exciting advances in modern medicinal chemistry, ranging from macrocyclic peptide oral PD-L1 inhibitors and IL-23R antagonists to next-generation small molecule CFTR modulators, pan-RAS molecular glues, and potential best-in-class orexin agonists. Their potential to combine biologic-like target engagement with the advantages of small molecule delivery is reshaping the druggable target space.

A key driver of this shift is the ability of macrocycles to address challenges that traditional small molecules struggle to overcome, including large, shallow, or highly dynamic protein surfaces such as PD-L1, RAS, IL-23R, CFTR, and OX2R. Innovations in conformational engineering, the understanding of chameleonicity, incorporation of non-canonical amino acids, lipidation, and formulation strategies make oral macrocyclic drugs increasingly feasible. Additionally, biocatalysis emerged as an attractive strategy by reducing step counts, delivering high stereoselectivity, and enabling more cost-effective and greener manufacturing of peptide macrocycles.

Innovative PK design emerged as a defining driver of drug discovery success in 2025. Strategic deuteration in deutivacaftor improved metabolic stability and extended half-life supporting once-daily dosing of next-generation CFTR modulator combinations. The incorporation of an unusual double spirocyclopropyl-cyclopropyl motif in vanzacaftor reduced an oxidative metabolism liability. Increasing the molecule's SMID (smallest maximum intramolecular distance) to mitigate CYP induction by limiting PXR activation demonstrated how subtle structural features can influence systemic drug-drug interaction potential.

Half-life extension was achieved through the introduction of HSA (human serum albumin)-binding motifs, as exemplified by BMS-986238, dramatically prolonging systemic exposure for oral macrocyclic peptides. In brensocatib, a reversible covalent amidoacetonitrile warhead with carefully tuned reactivity enabled sustained yet controlled inhibition of DPP1 by forming a reversible adduct with the catalytic Cys234 while attenuating nonspecific thiol reactivity. Intramolecular shielding of hydrogen bond donors in design of the high-molecular-weight BTK degrader bexobrutideg enhanced permeability to allow for robust CNS penetration, demonstrating how conformational control can overcome classical property-based limitations to exposure.