IRAK Degrader

APH02174 hemiformic is a highly selective and orally active IRAK4 PROTAC degrader with the DC₅₀ of 4.01 nM in THP-1 cells. APH02174 hemiformic blocks inflammatory signals by inhibiting IL-6 release. APH02174 hemiformic can be used for research on inflammatory conditions such as psoriasis vulgaris and rheumatoid arthritis.

Zomiradomide (KT-413) is an orally active IRAK4 PROTAC degrader with a DC₅₀ of 6 nM. Zomiradomide inhibits the NF-κB signaling pathway, while its molecular glue function mediates the degradation of Ikaros and Aiolos (with a DC₅₀ of 1 nM for both), activates the IFN-I signaling pathway, and selectively degrades IMiD substrates. Zomiradomide inhibits cancer cell proliferation and tumor growth. Zomiradomide can be used in research related to B-cell non-Hodgkin's lymphoma and diffuse large B-cell lymphoma.

JNJ-1013 is a potent and selective IRAK1 PROTAC degrader with an IC₅₀s of 72, 443, 1071 nM for IRAK1, IRAK4, VHL FP respectively. JNJ-1013 induces apoptosis and increases the expression of cleavaged PARP. JNJ-1013 decreases the expression IRAK1, p-IKBα, pSTAT3(Tyr705) (Pink: ligand for target protein (HY-138834); black: linker (HY-Y1760); Blue: E3 ligase ligand (HY-112078)).

PROTAC IRAK3 degrader-1 formic is a potent and selective IRAK3 degrader with a DC₅₀ of 0.002 μM. PROTAC IRAK3 degrader-1 formic induces proteasome-dependent degradation of IRAK3 via ternary complex formation with IRAK3 and CRBN. PROTAC IRAK3 degrader-1 formic can be used for cancer research.

PROTAC IRAK4 degrader-1 (compound I-210) is a Cereblon-based IRAK4 PROTAC degrader.

SB1-G-187 is a multi-target kinase PROTAC degrader with activity against various kinases including GCK, YES1, IRAK1 and LYN. SB1-G-187 induces degradation of target kinases via a p97-dependent pathway, and forms ternary complexes with CRBN and specific functional kinases. SB1-G-187 can be used in tumor-related research.

KTX-951 is an orally active PROTAC degrader of IRAK4 and IMiD (Ikaros/Aiolos) substrates (K_d = 3.5 nM). KTX-951 induces IRAK4 degradation, and the degradation efficiency is independent of IRAK4 binding affinity. The DC₅₀ values of KTX-951 for IRAK4, Ikaros and Aiolos are 18 nM, 14 nM and 13 nM, respectively. The IC₅₀ of KTX-951 against OCl-Ly10 CTG is 35 nM. KTX-951 exhibits antitumor activity.

PROTAC IRAK4 degrader-3 is a PROTAC-induced IRAK4 degrader based on von Hippel-Lindau.

PROTAC IRAK4 degrader-13 (Degrader 1) is a selective IRAK4 PROTAC degrader with DC₅₀s of 0.86 and 1.1 nM for monocytes and lymphocytes in PBMCs, respectively. PROTAC IRAK4 degrader-13 significantly induces TIR signal activation, and inhibits the expression of circulating proinflammatory cytokines in Imiquimod (HY-B0180) induced psoriasis mice model. PROTAC IRAK4 degrader-13 can be used for TLR- and IL-1R-driven driven neutrophilic inflammation diseases like hidradenitis suppurativa (HS) and atopic dermatitis (AD) research. Pink: IRAK4 ligand; Blue: E3 ligase ligand; Black: linker

PSP-0119 is a highly efficient and effective PROTAC degrader targeting IRAK4 (IC₅₀ = 2.83 nM). PSP-0119 can inhibit IRAK4 kinase activity, NF-κβ activity, and IL-1β-induced IRAK4 phosphorylation. PSP-0119 degrades IRAK4 in FLT3-mutant AML cell lines, sparing FLT3-wild-type AML cells, FLT3-wild-type samples, and normal bone marrow. PSP-0119 downregulates alpha-enolase (eNOS) of MOLM-13 cells. PSP-0119 can be used for the study of Acute Myeloid Leukemia (AML).

FIP22 is a potent and selective IRAK4 PROTAC degrader (HEK293T cells: DC₅₀ = 3.2 nM; THP-1 cells: DC₅₀ = 10.6 nM). FIP22 induces the ubiquitin-proteasome system by forming an IRAK4-FIP22-CRBN ternary complex (EC₅₀ = 12.63 nM), thereby potently blocking IRAK4-mediated NF-κB and MAPK signaling pathways. FIP22 can be used for the study of atopic dermatitis.

PROTAC IRAK4 degrader-8 (Compound 2) is a PROTAC degrader that targets IRAK4 by recruiting cereblon. PROTAC IRAK4 degrader-8 inhibits IRAK4 kinase activity with an IC₅₀ of 15.5 nM. PROTAC IRAK4 degrader-8 suppresses IL-6 production in immune cells. PROTAC IRAK4 degrader-8 can be used in the research of inflammatory diseases, immune diseases and cancers.

LZ-07 is a IRAK4 PROTAC degrader (DC₅₀ = 1.14 nM). LZ-07 leads to marked suppression of cytokines including IL-6, IL-1β, TNF-α, and IL-10 upon degradation of IRAK4. LZ-07 can be studied in research for autoimmune diseases (Pink: IRAK4 ligand (HY-172591); Blue: CRBN ligand (HY-34590); Black: linker (HY-B0149); CRBN ligand + linker: HY-172593).

KT-474 (KYM-001; PROTAC IRAK4 degrader-7) hydrochloride is an orally active PROTAC IRAK4 degrader with anti-tumor effects. KT-474 inhibits the cell cycle and induces apoptosis. KT-474 induces tumor regression in a xenograft model of MYD88-mutated ABC DLBCL.

APH02174 is a highly selective and orally active IRAK4 PROTAC degrader with the DC₅₀ of 4.01 nM in THP-1 cells. APH02174 blocks inflammatory signals by inhibiting IL-6 release. APH02174 can be used for research on inflammatory conditions such as psoriasis vulgaris and rheumatoid arthritis.

IRAK4 ligand-18 is a Ligand for Target Protein for PROTAC with antitumor activity. PROTAC IRAK4 ligand-4 can be used to synthesize PROTAC IRAK4 degrader-12 (HY-168586).

IRAK4 ligand-17 is a ligand for the target protein of PROTAC that targets IRAK4 (ligand for target protein for PROTAC), and it can be used for the synthesis of the PROTAC APH003 (HY-184915).

PROTAC IRAK4 degrader-12 is an orally active IRAK4 PROTAC degrader with a DC₅₀ of 4.87 nM in K562 IRAK4-HiBiT cells. PROTAC IRAK4 degrader-12 induces protein degradation of IRAK4, IKZF1 and IKZF3. It inhibits the proliferation of diffuse large B-cell lymphoma cells. It suppresses tumor growth in mouse xenograft models of lymphoma cells. PROTAC IRAK4 degrader-12 can be used for the research of B-cell lymphoma and diffuse large B-cell lymphoma.

PROTAC IRAK3 degrader-2 (Compound 17) is a IRAK3 PROTAC degrader with a DC₅₀ ≤ 50 nM. It promotes ubiquitination and degradation of IRAK3, and is applicable to the research of immune diseases.

APH003 is an orally active IRAK4 PROTAC degrader with a DC₅₀ of 0.74 nM in human peripheral blood mononuclear cells (hPBMCs). APH003 recruits IRAK4 to CRBN to form a ternary complex, mediates the ubiquitination and degradation of IRAK4 via the ubiquitin-proteasome pathway, and inhibits the kinase activity of IRAK4. APH003 inhibits LPS- or IL-1β/LPS-induced phosphorylation of ERK, JNK and NF-κB. APH003 inhibits the secretion of TNF-α, IL-6, IL-8 and IL-13 by stimulated hPBMCs. APH003 exhibits anti-inflammatory activity in rat TNBS-induced intestinal inflammation models and mouse IL-33-induced skin inflammation models. APH003 can be used in research related to inflammatory bowel disease and skin inflammation.