(1) Project name: Best-in-class IRAK4 Degrader

(2) Indications: Psoriasis, RA, Inflammatory bowel disease (IBD), or other autoimmune inflammatory diseases;

(3) Modality: PROTAC（Oral and local administration）

(4) Research phase: PCC

(5) Cooperation demands: License-out or co-development

IRAK4 PROTAC has proof of concept for autoimmune diseases
As the most upstream kinase in the Toll/IL-1 signaling cascade, IRAK4 has wide-ranging immune functions, and plays a central role in the pathophysiology of multiple autoimmune and inflammatory diseases；
IRAK4 has both kinase and scaffolding functions, and serves to assemble the myddosome, the complex that transmits signals from the Toll-like and interleukin receptors to promote an inflammatory response；
IRAK4 PROTAC eliminates both kinase-catalytic activity and scaffolding function, thus potentially achieving better efficacy than its SMIs；
The Phase I clinical data of KT-474 provide an important proof of conceptfor the advantages of IRAK4 degraders.
Molecule design strategy

Smaller size and lower weight of IRAK4 PROTACmolecule produces better pharmacokinetics profile, suitable for oral and local administration;
No hERG inhibitioneliminate atypical cardiac side effect risks which were observed in the phase I clinical trials of KT-474;
Better metabolic stability and oral bioavailability;
Faster and deeper degradation of IRAK4.

Good safety and tolerability with rats and dogs in non-GLP toxicity studies
IRAK4 protein degradation in a dose-dependent manner in rats and dogs ;
The body weight was normal in rats and dogs ;
hERGIC50>30μM, no abnormal ECG was observed in rats and dogs ;
No observed organ damages for heart, liver, spleen, lung, kidney and brain in rats and dogs ;The value of blood biochemical test (CK, LDH, ALT, AST, CREA,UREA) and blood routine test were innormal range in rats
The value of blood biochemical test (CK, LDH, ALT, AST, CREA, UREA, Glu, TBIL) and coagulationaction test (APTT, PT, TT, Fib) were in normal range in dogs
Better oral bioavailability in mice, rats and dogs
Faster and deeper degradation of IRAK4 in vivo

Better efficacy on various models of IMQ, CIA and DSS under lower dosage
IMQmodel: Better efficacy under lower dosage via oral administration; Good efficacy via local administration;
CIA model: QD, lower dosage, better degradation and disease progress control;
DSS model: Asset displayed much better efficacy than KT-474 under QD and lower dosage