7C2V
Crystal Structure of IRAK4 kinase in complex with the inhibitor CA-4948
Summary for 7C2V
| Entry DOI | 10.2210/pdb7c2v/pdb |
| Descriptor | Interleukin-1 receptor-associated kinase 4, 2-(2-methylpyridin-4-yl)-N-[2-morpholin-4-yl-5-[(3R)-3-oxidanylpyrrolidin-1-yl]-[1,3]oxazolo[4,5-b]pyridin-6-yl]-1,3-oxazole-4-carboxamide (3 entities in total) |
| Functional Keywords | irak4, inhibitor, ca-4948, kinase, cell cycle, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 137394.26 |
| Authors | Krishnamurthy, N.R.,Robert, B. (deposition date: 2020-05-09, release date: 2020-11-25, Last modification date: 2024-11-20) |
| Primary citation | Gummadi, V.R.,Boruah, A.,Ainan, B.R.,Vare, B.R.,Manda, S.,Gondle, H.P.,Kumar, S.N.,Mukherjee, S.,Gore, S.T.,Krishnamurthy, N.R.,Marappan, S.,Nayak, S.S.,Nellore, K.,Balasubramanian, W.R.,Bhumireddy, A.,Giri, S.,Gopinath, S.,Samiulla, D.S.,Daginakatte, G.,Basavaraju, A.,Chelur, S.,Eswarappa, R.,Belliappa, C.,Subramanya, H.S.,Booher, R.N.,Ramachandra, M.,Samajdar, S. Discovery of CA-4948, an Orally Bioavailable IRAK4 Inhibitor for Treatment of Hematologic Malignancies. Acs Med.Chem.Lett., 11:2374-2381, 2020 Cited by PubMed Abstract: Small 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 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. PubMed: 33335659DOI: 10.1021/acsmedchemlett.0c00255 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.44 Å) |
Structure validation
Download full validation report
