Key drug target

LONDON—Scientists from Heptares Therapeutics, a subsidiary of Sosei Group Corporation, have solved the high-resolution X-ray crystal structure of the CCR9 receptor, a member of the chemokine receptor family, according to a recently published article in Nature.

As the article “Intracellular allosteric antagonism of the CCR9 receptor” explained, “Chemokines and their G-protein-coupled receptors play a diverse role in immune defense by controlling the migration, activation and survival of immune cells. They are also involved in viral entry, tumor growth and metastasis and hence are important drug targets in a wide range of diseases.”

The CCR9 receptor itself is central to leukocyte (white blood cell) recruitment to the gut. It represents a therapeutic target in inflammatory bowel diseases, an area of increasing interest for Heptares.

“Despite very significant efforts by the pharmaceutical industry to develop drugs, with over 50 small-molecule drugs directed at the family entering clinical development, only two compounds have reached the market: maraviroc (CCR5) for HIV infection and plerixafor (CXCR4) for stem-cell mobilization,” the article stated. The authors attributed the high failure rate to “the limited understanding of the mechanism of action of chemokine antagonists and an inability to optimize compounds in the absence of structural information.” They believe that the new information could improve the success rate of efforts to develop small-molecule therapeutics against chemokine receptors.

According to Fiona Marshall, chief scientific officer at Heptares and at Sosei, “The availability of a high-resolution structure of the CCR9 receptor in this conformation provides a unique opportunity to apply structure-based drug design to the discovery and optimization of selective small-molecule allosteric modulator drugs not only targeting CCR9 but potentially also other members of the chemokine receptor family. This new structural information adds to the wealth of information the company has generated using its StaR platform on GPCRs, and is enabling the company to apply its structure-based design platform to develop a sustainable pipeline of novel drug candidates in diverse disease areas.”

The scientists devised and performed the conformational thermostabilization and mutagenesis of the receptor, characterized expression constructs and performed radioligand binding analysis of mutants. They then performed computational analysis of the structure and modeling. The scientists established the platform/protocols for LCP crystallization and solved the structure and then supported expression and scouted purification of the final StaR. They designed and characterized all constructs, collected and processed X-ray diffraction data and solved the structure. Next they optimized purification, performed LCP crystallization, harvested crystals, collected and processed X-ray diffraction data, solved and refined the structure and performed and analyzed the pharmacology data.

As the article explained, “The selective CCR9 antagonist vercirnon progressed to Phase 3 clinical trials in Crohn’s disease, but efficacy was limited, with the need for very high doses to block receptor activation.” The scientists explained how they solved the X-ray structure of the CCR9 receptor bound to vercirnon. The research showed that, surprisingly, vercirnon binds to the intracellular side of the receptor and not to the normal binding site for GPCR ligands. In binding to this allosteric site on CCR9, vercirnon exerts its antagonistic effect by preventing CCR9 from interacting with signaling molecules inside the cell.

Previously, Heptares scientists identified allosteric binding sites on other GPCRs including the glucagon receptor. Now they believe that this “breakthrough finding” has “opened a new avenue for investigation across the chemokine receptor family.”