GPR20 (G Protein-Coupled Receptor 20)

The N-terminal cap of GPR20 functions like an agonist and mediates long-range activated conformational shift. Together with the previous study, this study enhances our knowledge of the self-activation mechanism of the orphan receptor, facilitates the drug discovery efforts that target GPR20.

P1, N=34, Terminated, Daiichi Sankyo | Completed --> Terminated; The study was terminated due to a business decision.

Targeting GPR20 with DS-6157a was tolerated in patients with advanced GIST with tumor shrinkage demonstrated in KIT/PDGFRA wild type GIST. However, the study did not proceed further due to lower efficacy outcomes than anticipated.

We also uncover the molecular interactions between GPR20 and Ab046, which may enable the design of tool antibodies with enhanced affinity or new functionality for GPR20. Furthermore, we report the orthosteric pocket occupied by an unassigned density which might be essential for exploring opportunities for deorphanization.

P1, N=35, Completed, Daiichi Sankyo, Inc. | Active, not recruiting --> Completed

P1, N=34, Active, not recruiting, Daiichi Sankyo, Inc. | N=100 --> 34 | Trial completion date: Oct 2024 --> May 2022 | Trial primary completion date: May 2024 --> Jan 2022

P1, N=100, Active, not recruiting, Daiichi Sankyo, Inc. | Recruiting --> Active, not recruiting

GPRs role in liver disease is intriguing and a field of research opportunity. More studies are necessary to define the role of active fatty acids in the development of metabolic diseases.

DS-6157a exhibited GPR20 expression-dependent antitumor activity in GIST xenograft models including a GIST model resistant to imatinib, sunitinib, and regorafenib. Pre-clinical pharmacokinetics and safety profile of DS-6157a support its clinical development as a potential novel GIST therapy in patients with resistance, refractory, or intolerance to approved TKIs.

In addition, DS-6157a showed antitumor activity in a GIST patient-derived xenograft model that was resistant to imatinib, sunitinib, and regorafenib. In preclinical toxicology studies using rats and cynomolgus monkeys, the pharmacokinetics and safety profile of DS-6157a were favorable at up to 200 mg/kg and 30 mg/kg, respectively. These data support the clinical development of DS-6157a as a potential novel GIST therapy with activity in patients that are resistant, refractory, or intolerant to approved TKIs.

P1, N=100, Not yet recruiting, Daiichi Sankyo, Inc. | Trial completion date: Mar 2025 --> Oct 2024 | Trial primary completion date: Mar 2025 --> May 2024

P1, N=100, Recruiting, Daiichi Sankyo, Inc. | Not yet recruiting --> Recruiting