P1, N=27, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | Initiation date: Feb 2025 --> Nov 2025

P2, N=195, Terminated, Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Recruiting --> Terminated | Trial primary completion date: Jun 2024 --> Jan 2025; Per sponsor request.

P1, N=25, Not yet recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2025 --> Jun 2027 | Trial primary completion date: Oct 2025 --> Jun 2027

P1/2, N=152, Recruiting, Curis, Inc. | N=80 --> 152

P1/2, N=34, Recruiting, Rigel Pharmaceuticals | Phase classification: P1b --> P1/2

P1, N=42, Recruiting, Washington University School of Medicine | Trial completion date: Jun 2027 --> Jun 2028 | Trial primary completion date: Sep 2026 --> Sep 2027

In this paper, we will provide a detailed description of the structure and function of IRAK4, the role of IRAK4 in related diseases, as well as the currently reported small molecule inhibitors and degraders of IRAK4. It is expected to provide new directions for enriching the clinical treatment of inflammation and related diseases.

P1, N=39, Completed, AstraZeneca | Active, not recruiting --> Completed

P1, N=39, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting

P1, N=93, Completed, AstraZeneca | Recruiting --> Completed

The potent IRAK4 inhibitor CA-4948 has shown efficacy in both pre-clinical studies and MDS clinical trials, with splicing factor mutant patients showing the higher response rates. Emerging data has, however, revealed that co-targeting of IRAK4 and its paralog IRAK1 is required to maximally suppress LSPC function in vitro and in vivo by inducing cellular differentiation. These findings provide a link between the presence of the commonly mutated splicing factor genes and activation of innate immune signaling pathways in myeloid malignancies and have important implications for targeted therapy in these disorders.

P1, N=17, Completed, AstraZeneca | Active, not recruiting --> Completed

P2, N=33, Recruiting, Gilead Sciences | Trial completion date: Dec 2024 --> Sep 2025 | Trial primary completion date: Dec 2024 --> Aug 2025

Our findings suggest that ART can significantly reduce OPC perinatal inflammation and consequent oxidative stress. The targeted inhibition of IRAK-4 and IRAK-1 by ART may be a potential therapeutic strategy for alleviating abnormalities in white matter development in premature newborns.

P1, N=8, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting | N=18 --> 8

P1, N=18, Recruiting, AstraZeneca | N=48 --> 18

P2, N=38, Terminated, University of Leipzig | Trial completion date: Mar 2024 --> Jul 2024 | Trial primary completion date: Mar 2024 --> Jul 2024

P1, N=48, Recruiting, AstraZeneca | Not yet recruiting --> Recruiting | N=16 --> 48

P1, N=93, Recruiting, AstraZeneca | N=133 --> 93

P1, N=25, Not yet recruiting, National Cancer Institute (NCI) | Initiation date: Aug 2024 --> Dec 2024

P1, N=16, Not yet recruiting, AstraZeneca

Additionally, molecular dynamics simulations confirmed the stable binding of the screened compounds to the IRAK4 protein. Overall, this work presents a machine learning model for accurate prediction of IRAK4 inhibitor activity and offers new insights for subsequent structure-guided design of novel IRAK4 inhibitors.

P1, N=80, Recruiting, Eilean Therapeutics | N=40 --> 80

P1, N=25, Not yet recruiting, National Cancer Institute (NCI)

P1, N=40, Recruiting, AstraZeneca | Not yet recruiting --> Recruiting

P2, N=38, Terminated, University of Leipzig | N=84 --> 38 | Trial completion date: Apr 2025 --> Mar 2024 | Recruiting --> Terminated; First interim analysis for cohort A performed, due to safety concerns cohort B closed prematurely

P1, N=64, Recruiting, Eilean Therapeutics

Herein, we describe the discovery of a series of pyridone analogs with improved solubility which are highly potent, selective and demonstrate desirable PK profiles including good oral bioavailability and excellent brain penetration. BIO-8169 (2) reduced the in vivo production of pro-inflammatory cytokines, was well tolerated in safety studies in rodents and dog at margins well above the predicted efficacious exposure and showed promising results in a mouse model for multiple sclerosis.

P1/2, N=29, Recruiting, University of Florida | Not yet recruiting --> Recruiting

The FLT3 and IRAK4 inhibitor emavusertib (CA4948), the MCL1 inhibitor S63845, the BCL2 inhibitor venetoclax, and the HSP90 inhibitor PU-H71 were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells in vitro. The combination of CA4948 and BH3-mimetics may be effective in the treatment in FLT3-mutated AML with differential target specificity for MCL1 and BCL2 inhibitors. Moreover, the combination of CA4948 and PU-H71 may be a candidate combination treatment in FLT3-mutated AML.

P1, N=60, Not yet recruiting, Eilean Therapeutics

P1, N=40, Not yet recruiting, AstraZeneca

P1, N=3, Terminated, Gilead Sciences | Phase classification: P1b --> P1

Receiver operating characteristics (ROC) analysis and area under the curve (AUC) suggested that the expression of TLR2, TLR4, and IRAK4 (AUC = 0.702, AUC = 0.75, and AUC = 0.682, respectively) had acceptable diagnostic values to identify MDS from the other understudied leukemias. Overall, the expression of TLR2, TLR4, and IRAK4 could be potential biomarkers for discriminating MDS from some hematologic disorders.

Finally, pharmacological targeting of interleukin-1 receptor-associated kinase 4 (IRAK4) with inhibitor CA-4948 suppressed disease burden and inflammatory cytokines specifically in MPN without inducing toxicity in non-diseased models. These findings highlight vulnerabilities in MPN that are exploitable with emerging therapeutic approaches.

P2, N=77, Completed, Bayer | Active, not recruiting --> Completed

P1, N=133, Recruiting, AstraZeneca | Trial completion date: Mar 2024 --> Sep 2024 | Trial primary completion date: Mar 2024 --> Sep 2024

P1, N=63, Completed, Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Recruiting --> Completed | Trial completion date: Dec 2023 --> May 2023

P1/2, N=29, Not yet recruiting, University of Florida

The loss of IRAK4, of IRAK4 kinase activity, of either Pellino protein, or of the nuclear localization sequence in IRAK1 sensitized p53-mutant zebrafish to radiation. Thus, the findings may lead to strategies for overcoming tumor resistance to conventional cancer treatments.

The loss of important ligand residue-wise contacts, altered protein global flexibility, increased steric clashes, and even electronic penalties at the ligand-binding site interfaces were all suggested to be associated with SNP models for hampering the HG-12-6 affinity towards IRAK4 target protein. This given model lays the foundation for the better prediction of various disorders relevant to IRAK4 malfunction and sheds light on the impact of deleterious IRAK4 variants on IRAK4 inhibitor efficacy.

Provided herein are novel IRAK4 inhibitors, pharmaceutical compositions, use of such compounds in treating asthma, COPD, cancer, autoinflammatory diseases, and autoimmune diseases, and processes for preparing such compounds.