Pharmacology articles from across Nature Portfolio

Blockade of primary genomic binding sites with small molecules causes redistribution of the transcription factor PU.1 to alternative binding sites; its transcriptional activity at these sites activates secondary gene networks that drive myeloid cell differentiation.

The voltage-gated potassium (Kv) channel formed by Kv7.2/3 heteromers is a major target for anticonvulsant drug development, however, specificity and potency are key challenges for Kv7.2/3 opener development. Here, the authors report the discovery of gentisic acid as a potent and selective Kv7.3 opener from Thespesia populnea — a plant reportedly used as an anticonvulsant in Polynesian traditional medicine.

EDI048 is a gastrointestinal-targeted Cryptosporidium PI(4)K inhibitor that undergoes a predictable metabolism and limits systemic exposure without compromising its anti-parasitic activity.

Metabotropic glutamate (mGlu) receptors form both homo- and heterodimers that respond to ligands differently. Here, the authors elucidate the mechanism of activation and differential pharmacology in mGlu_2/4 heteromers, which may guide targeted therapy.

Pharmacological therapies with incretin-based ‘multi-agonists’ are rapidly advancing the therapeutic landscape for obesity. The loss of skeletal muscle mass with these potent weight-loss agents is emerging as a possible side effect. It is therefore important to determine whether multi-agonists increase the risk of sarcopenia in susceptible patients.

Blockade of primary genomic binding sites with small molecules causes redistribution of the transcription factor PU.1 to alternative binding sites; its transcriptional activity at these sites activates secondary gene networks that drive myeloid cell differentiation.

The anti-apoptotic protein MCL1 is a therapeutic target in cancer, but long-term MCL1 inhibition has been found to increase the risk of cardiotoxicity. We developed BRD-810 as a potent and selective MCL1 inhibitor that induces cancer cell death in vivo within a few hours. As BRD-810 was designed to be rapidly cleared, it targets cancer cells while minimizing the risk for cardiotoxicity.

RAS proteins, central drivers of cancer, appeared ‘undruggable’ for almost 30 years. Here we provide a personal perspective on the effort leading to our initial report of KRAS^G12C inhibitors in 2013, and the decade of discoveries that followed.

Anti-obesity medications based on incretin hormones have advanced weight control and metabolic health in individuals with obesity. The long-term success of obesity therapeutics could be facilitated by exercise, a vital metabolic ally in enhancing treatment efficacy.