science

We Interrogate The Inner Life Of GPCR Signaling To Develop New Therapeutics

The team at Crinetics has a depth of expertise not only in small molecule drug discovery and development for endocrine diseases, but also in the dynamic behavior and alternative signaling of neuropeptides and G-protein coupled receptors (GPCRs).

Crinetics has delved deep into the understanding the inner life of GPCRs to tailor and optimize drug candidates to specific diseases.

For decades it was thought that GPCRs function as simple on-off switches, but GPCRs have a complex and diverse inner life. Many lines of recent research have shown that distinct signaling cascades and feedback mechanisms create multi-dimensional pathways with distinct physiological responses. These different behaviors are based on receptor trafficking, ligand binding, and biased agonism. Understanding these different GPCR signaling paradigms provides new opportunities to modulate GPCR activities that we think will lead to therapeutics that are more effective with fewer side effects.

Neuropeptides And Functional Selectivity: A New Paradigm To Modulate GPCR Signaling

Neuropeptides are a diverse family of peptides and proteins that are involved in a wide range of functions in human physiology and disease. Neuropeptides act almost exclusively at specific GPCRs and execute their very precise control over human physiology through multiple signaling pathways.

Most currently available drugs that target neuropeptide receptors are first generation biologics (stabilized peptides) that require often-painful/inconvenient daily, weekly, or monthly injections.

At Crinetics, we have a significant advantage. With our GPCR research, medicinal chemistry, and pharmacology expertise, we can specifically target GPCRs with small molecules and overcome the issues of these first generation biologics.

Crinetics is developing novel, small molecule, orally available drugs that target neuropeptide receptors. Our first programs target somatostatin and kisspeptin receptors.

Learn more about or therapeutic programs in acromegaly, neuroendocrine tumors, Cushing’s Disease, hyperinsulinism, and chronic pain.

Relevant Publications

  • Refining efficacy: allosterism and bias in G protein-coupled receptor signaling.
    Luttrell LM, Kenakin TP. Methods in Molecular Biology. 2011; 756:3-35.

  • Structure-based discovery of opioid analgesics with reduced side effects.

    Manglik A, Lin H, Aryal DK, McCorvy JD, Dengler D, Corder G, Levit A, Kling RC, Bernat V, Hübner H, Huang XP, Sassano MF, Giguère PM, Löber S, Da Duan, Scherrer G, Kobilka BK, Gmeiner P, Roth BL, Shoichet BK. Nature. 2016; 537:185-190. 


  • Fulfilling the promise of "biased" G protein-coupled receptor agonism.
    Luttrell LM, Maudsley S, Bohn LM. Molecular Pharmacology. 2015; 88:579-88.