7jra
From Proteopedia
HUMAN TNF-ALPHA IN COMPLEX WITH 2-[5-(3-chloro-4-{[(1R)-1-(2-fluorophenyl)ethyl]amino}quinolin-6-yl)pyrimidin-2-yl]propan-2-ol
Structural highlights
DiseaseTNFA_HUMAN Genetic variations in TNF are a cause of susceptibility psoriatic arthritis (PSORAS) [MIM:607507. PSORAS is an inflammatory, seronegative arthritis associated with psoriasis. It is a heterogeneous disorder ranging from a mild, non-destructive disease to a severe, progressive, erosive arthropathy. Five types of psoriatic arthritis have been defined: asymmetrical oligoarthritis characterized by primary involvement of the small joints of the fingers or toes; asymmetrical arthritis which involves the joints of the extremities; symmetrical polyarthritis characterized by a rheumatoidlike pattern that can involve hands, wrists, ankles, and feet; arthritis mutilans, which is a rare but deforming and destructive condition; arthritis of the sacroiliac joints and spine (psoriatic spondylitis). FunctionTNFA_HUMAN Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation.[1] The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells.[2] Publication Abstract from PubMedScaffold hopping and structure-based drug design were employed to identify substituted 4-aminoquinolines and 4-aminonaphthyridines as potent, small molecule inhibitors of tumor necrosis factor alpha (TNFalpha). Structure-activity relationships in both the quinoline and naphthyridine series leading to the identification of compound 42 with excellent potency and pharmacokinetic profile are discussed. X-ray co-crystal structure analysis and ultracentrifugation experiments clearly demonstrate that these inhibitors distort the TNFalpha trimer upon binding, leading to aberrant signaling when the trimer binds to TNF receptor 1 (TNFR1). Pharmacokinetic-pharmacodynamic activity of compound 42 in a TNF-induced IL-6 mouse model and in vivo activity in a collagen antibody-induced arthritis model, where it showed biologic-like in vivo efficacy, will be discussed. Biologic-like In Vivo Efficacy with Small Molecule Inhibitors of TNFalpha Identified Using Scaffold Hopping and Structure-Based Drug Design Approaches.,Xiao HY, Li N, Duan JJ, Jiang B, Lu Z, Ngu K, Tino J, Kopcho LM, Lu H, Chen J, Tebben AJ, Sheriff S, Chang CY, Yanchunas J Jr, Calambur D, Gao M, Shuster DJ, Susulic V, Xie JH, Guarino VR, Wu DR, Gregor KR, Goldstine CB, Hynes J Jr, Macor JE, Salter-Cid L, Burke JR, Shaw PJ, Dhar TGM J Med Chem. 2020 Dec 1. doi: 10.1021/acs.jmedchem.0c01732. PMID:33261314[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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