1.Design Strategy

Although multiple biologics and conventional small molecule drugs have improved the treatment and management of Ulcerative Colitis (UC) and Crohn's Disease (CD), these therapies are only effective for a portion of IBD patients and prone to loss of efficacy.
There are some safety concerns, with an increased risk of serious adverse events (such as severe infections and cardiovascular events) and malignancies.
Receptor-interacting protein kinase 2 (RIPK2) is an essential regulator of the inflammatory process and immune response.

RIPK2 is a downstream signaling molecule of nucleotide-binding oligomerization domain-containing proteins 1 and 2 (NOD1/2) and plays a crucial role in regulating NOD-mediated inflammatory responses
In innate immunity, the NOD-RIPK2 signaling axis is an important pathway that directly mediates inflammation and immune response.
In adaptive immunity, RIPK2 may affect T cell proliferation, differentiation and cellular homeostasis thereby involving T cell-driven autoimmunity.
The expression of RIPK2 protein dramatically increased in pathological tissue of IBD patients
Emerging robustevidence supports the idea that NOD-RIPK2 pathway-mediated inflammatory response plays a critical role in the development of IBD.
The asset is a novel therapy thattargets RIPK2 for IBD treatment

2.Results and Data

Asset (UPC-021-05&UPC-013-05) potently degrade RIPK2 with a DC₅₀of ~1 nM in THP-1 cell

Asset highly selective degrade RIPK2, but not the homologs of RIPK2 (RIPK1/3) and neo-targets of iMIDs (GSPT1, IKZF1/3).
Greatefficacy with no toxicity in rodents
TNBS induced CRBN mice model
Asset significantly improved DAI scores and showed comparable efficacy withor even better efficacy than Mesalazine

Asset significantly mitigated emaciation and markedly countered the weight and density increases of colon caused by acute inflammation
Asset significantly improved histopathology scores (colon HE staining) to a level comparable to typical Mesalazineand much better than Upadacitinib
Asset demonstrated superior suppression of the pro-inflammatory factorIL-1β, TNFα and IL-6 compared to the extremely potent Mesalazine batch
DSS-induced mousecolitis model
Asset significantly improved key parameters, including body weight, colon length, and colon weight,compared with Sulfasalazine and Olsalazine
Asset accumulated in the intestinal tissue, approximately 300 times than in blood
Excellentsafety profile:
No hERG liability
No abnormalities were observed