7C2W

Crystal Structure of IRAK4 kinase in complex with a small molecule inhibitor

7C2W の概要

• エントリーDOI: 10.2210/pdb7c2w/pdb
• 分子名称: Interleukin-1 receptor-associated kinase 4, N-(2-morpholin-4-yl-1,3-benzoxazol-6-yl)-6-pyridin-4-yl-pyridine-2-carboxamide (3 entities in total)
• 機能のキーワード: irak4, inhibitor, ca-4948, kinase, cell cycle, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 135272.74

構造登録者

Krishnamurthy, N.R.,Anirudha, L. (登録日: 2020-05-09, 公開日: 2020-11-25, 最終更新日: 2023-11-29)

主引用文献

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

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: 33335659
DOI: 10.1021/acsmedchemlett.0c00255

実験手法

X-RAY DIFFRACTION (3.2 Å)