Molecular Targets

Molecular targets are the macromolecules in cells—principally proteins, but also nucleic acids—that underlie disease processes and can be modulated by therapeutic agents. By binding to an enzyme’s active site, stabilising an inactive receptor conformation or blocking a transporter, a small-molecule drug or biologic achieves a desired change in cell function or physiological state. Broad target classes include enzymes (oxidoreductases, transferases, hydrolases, lyases, isomerases and ligases), receptors (G-protein-coupled, ion-gated, tyrosine kinase and nuclear), membrane transporters, ion channels and regulatory nucleic acids. Each offers distinct modes of action: enzymes can be inhibited competitively, non-competitively or allosterically and may be reversible or, more rarely, irreversible targets; receptors respond to agonists, antagonists or inverse agonists; transporters and channels permit active or passive fluxes of ions or metabolites. Rational drug discovery exploits structural and mechanistic knowledge of a chosen target to design and optimise chemical ligands, while phenotypic approaches screen for functional effects first and deconvolute the target afterwards. A deep understanding of the three-dimensional binding pocket, the transition-state geometry for enzyme catalysis or the conformational switch in receptor activation underpins the selection of high-value targets and the design of potent and selective modulators.

Research from Nature Portfolio

Recent clinical advances have been reported for small-molecule inhibitors of mutant isocitrate dehydrogenase (mIDH1). In a perioperative phase I trial of patients with nonenhancing mIDH1 low-grade gliomas, two inhibitors achieved over 90 percent reduction of the oncometabolite 2-hydroxyglutarate in tumour tissue. Suppression of 2-hydroxyglutarate was accompanied by reversal of DNA hypermethylation and attenuation of gene programmes linked to stemness and proliferation. One compound demonstrated superior brain penetrance, favourable safety and preliminary immune activation, and has advanced into phase III testing for newly diagnosed cases.

Cancer cell-intrinsic signalling by immune checkpoints has emerged as a distinct target class. A recent Perspective summarises how PD-L1, long known for inhibitory interactions with T cells, also engages intracellular pathways that control tumour growth, survival, stemness and resistance to therapy in a PD-1-independent manner. These cell-intrinsic PD-L1 signals present novel drug discovery opportunities beyond extracellular immune-checkpoint blockade.

Alteration of the tumour microenvironment by targeting stromal remodelling enzymes has shown promise. A first-in-class pan-lysyl oxidase inhibitor was found to inhibit collagen cross-linking, decrease matrix stiffness and reduce metastatic dissemination in preclinical pancreatic cancer models. When combined with gemcitabine, this agent improved tumour perfusion, enhanced chemotherapy efficacy and extended survival, validating lysyl oxidases as druggable mediators of desmoplasia and chemoresistance.

Molecular Targets publication trend

The graph below shows the total number of articles in molecular targets across all publications each year (not limited to Nature Index journals).

Technical terms

Enzyme: A protein catalyst that accelerates a chemical reaction by stabilising the transition state; subdivided into classes such as oxidoreductases, transferases and hydrolases.

G-protein-coupled receptor (GPCR): A seven-pass transmembrane receptor that, upon ligand binding, activates intracellular G-proteins to regulate second-messenger pathways.

Allosteric modulator: A compound that binds to a site distinct from the orthosteric (active) site to alter protein conformation and function.

Transition state: The high-energy, short-lived configuration of substrate atoms at the peak of the activation energy barrier in an enzyme-catalysed reaction.

Oncometabolite: A metabolite whose accumulation—often due to mutated metabolic enzymes—drives epigenetic and metabolic reprogramming that promotes cancer.

Desmoplasia: The fibrotic stromal reaction around a tumour, characterised by increased collagen deposition and matrix cross-linking, which can impede drug delivery.

Phenotypic screening: An unbiased approach in which compounds are tested for desired cellular or organismal effects first, with molecular targets identified afterward.

References

1. Target Discovery.
2. Vorasidenib and ivosidenib in IDH1-mutant low-grade glioma: a randomized, perioperative phase 1 trial. Nature Medicine (2023).
3. Programmed death ligand 1 signals in cancer cells. Nature Reviews Cancer (2022).
4. A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer. Nature Cancer (2023).
5. Tryptophan deficiency induced by indoleamine 2,3‐dioxygenase 1 results in glucose transporter 1‐dependent promotion of aerobic glycolysis in pancreatic cancer. MedComm (2024).
6. Proximity proteome mapping reveals PD-L1-dependent pathways disrupted by anti-PD-L1 antibody specifically in EGFR-mutant lung cancer cells. Cell Communication and Signaling (2023).
7. Redrawing Urokinase Receptor (uPAR) Signaling with Cancer Driver Genes for Exploring Possible Anti-Cancer Targets and Drugs. Pharmaceuticals (2023).