7c2v
Crystal Structure of IRAK4 kinase in complex with the inhibitor CA-4948Crystal Structure of IRAK4 kinase in complex with the inhibitor CA-4948
Structural highlights
DiseaseIRAK4_HUMAN Defects in IRAK4 are the cause of recurrent isolated invasive pneumococcal disease type 1 (IPD1) [MIM:610799. Recurrent invasive pneumococcal disease (IPD) is defined as two episodes of IPD occurring at least 1 month apart, whether caused by the same or different serotypes or strains. Recurrent IPD occurs in at least 2% of patients in most series, making IPD the most important known risk factor for subsequent IPD.[1] Defects in IRAK4 are the cause of IRAK4 deficiency (IRAK4D) [MIM:607676. IRAK4 deficiency causes extracellular pyogenic bacterial and fungal infections in otherwise healthy children.[2] [3] FunctionIRAK4_HUMAN Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways. Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation to form the Myddosome together with IRAK2. Phosphorylates initially IRAK1, thus stimulating the kinase activity and intensive autophosphorylation of IRAK1. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates NCF1 and regulates NADPH oxidase activation after LPS stimulation suggesting a similar mechanism during microbial infections.[4] [5] [6] [7] [8] [9] [10] Publication Abstract from PubMedSmall molecule potent IRAK4 inhibitors from a novel bicyclic heterocycle class were designed and synthesized based on hits identified from Aurigene's compound library. The advanced lead compound, CA-4948, demonstrated good cellular activity in ABC DLBCL and AML cell lines. Inhibition of TLR signaling leading to decreased IL-6 levels was also observed in whole blood assays. CA-4948 demonstrated moderate to high selectivity in a panel of 329 kinases as well as exhibited desirable ADME and PK profiles including good oral bioavailability in mice, rat, and dog and showed >90% tumor growth inhibition in relevant tumor models with excellent correlation with in vivo PD modulation. CA-4948 was well tolerated in toxicity studies in both mouse and dog at efficacious exposure. The overall profile of CA-4948 prompted us to select it as a clinical candidate for evaluation in patients with relapsed or refractory hematologic malignancies including non-Hodgkin lymphoma and acute myeloid leukemia. Discovery of CA-4948, an Orally Bioavailable IRAK4 Inhibitor for Treatment of Hematologic Malignancies.,Gummadi VR, Boruah A, Ainan BR, Vare BR, Manda S, Gondle HP, Kumar SN, Mukherjee S, Gore ST, Krishnamurthy NR, Marappan S, Nayak SS, Nellore K, Balasubramanian WR, Bhumireddy A, Giri S, Gopinath S, Samiulla DS, Daginakatte G, Basavaraju A, Chelur S, Eswarappa R, Belliappa C, Subramanya HS, Booher RN, Ramachandra M, Samajdar S ACS Med Chem Lett. 2020 Oct 14;11(12):2374-2381. doi:, 10.1021/acsmedchemlett.0c00255. eCollection 2020 Dec 10. PMID:33335659[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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