Background: VAV1, a Rho-family guanine nucleotide exchange factor is mainly expressed in immune cells and a key signaling molecule downstream of both the T and B cell receptors. Loss of function mutation of VAV1 abrogates inflammation, tissue damage, and disease progression in mouse models of arthritis and EAE. Drugging VAV1 is challenging by conventional small molecule, protein degradation by molecule glue offers a novel therapeutic modality to reduce VAV1 expression and modulate T and B cell function. Here we report a highly potent VAV1 molecular glue degrader GS25-B005 that selectively targets VAV1 for proteasomal degradation.

Methods: The in vitro activity of GS25-B005 was conducted using human and mouse blood cells for VAV1 levels and selectivity. Functional endpoints were assayed in purified human T cells and B cells following stimulation of their respective TCRs and BCRs. The in vivo activity of GS25-B005 was evaluated in the KLH TDAR mouse model, and levels of anti-KLH IgM and anti-KLH IgG as well as VAV1 protein levels in peripheral blood cells were assessed ex vivo.

Results: In vitr o, GS25-B005 demonstrated about 15-fold more potent activity (sub-nanomolar level DC50) than MRT-6160 in human cells. In addition, GS25-B005 showed cross-species degradation activities in mouse and human blood cells, and similar activities in mouse blood and splenocytes. Furthermore, GS25-B005 exhibited significantly better inhibition of T and B cell function than MRT-6160 . GS25-B005 also demonstrated favorable ADME profile, clean safety panel, excellent oral bioavailability and high plasma exposure across multiple species. Finally, GS25-B005 achieved a superior target degradation and more robust in vivo inhibition of anti-KLH IgG production than MRT-6160 or CsA in a KLH TDAR mouse model. Besides, 28-day rat toxicological data of GS25-B005 showed favorable safety profiles.

Conclusions: GS25-B005 has shown potent activity in both in vitro degradation and in vivo inhibition of IgG in a KLH-induced TDAR mouse model, in comparison to MRT-6160 , a competitor molecule currently in Ph1 study. These data suggest that GS25-B005 -mediated degradation of VAV1 has therapeutic potential in T and B cell-mediated autoimmunity and chronic inflammatory diseases.

REFERENCES: NIL.

Acknowledgments: NIL.

Disclosure of Interests: Meng Liu Changchun GeneScience Pharmaceutical Co., Ltd., Kaijun Geng Changchun GeneScience Pharmaceutical Co., Ltd., Chen Zhang Changchun GeneScience Pharmaceutical Co., Ltd. Shang hai, China, BO QU Changchun GeneScience Pharmaceutical Co., Ltd., Biao Lu Changchun GeneScience Pharmaceutical Co., Ltd., Fanglong Yang Changchun GeneScience Pharmaceutical Co., Ltd., Yuanfeng Xia Changchun GeneScience Pharmaceutical Co., Ltd., XIAOZHEN WANG Changchun GeneScience Pharmaceutical Co., Ltd., GULIANG XIA Changchun GeneScience Pharmaceutical Co., Ltd., Siqin Wang Changchun GeneScience Pharmaceutical Co., Ltd. Shang hai, China, Lei Jin Changchun GeneScience Pharmaceutical Co., Ltd. Shang hai, China.