5w5o | pdb_00005w5o
Identification of potent and selective RIPK2 inhibitors for the treatment of inflammatory diseases.
Structural highlights
Function[RIPK2_HUMAN] Serine/threonine/tyrosine kinase that plays an essential role in modulation of innate and adaptive immune responses. Upon stimulation by bacterial peptidoglycans, NOD1 and NOD2 are activated, oligomerize and recruit RIPK2 through CARD-CARD domains. Once recruited, RIPK2 autophosphorylates and undergoes 'Lys-63'-linked polyubiquitination by E3 ubiquitin ligases BIRC2 and BIRC3. The polyubiquitinated protein mediates the recruitment of MAP3K7/TAK1 to IKBKG/NEMO and induces 'Lys-63'-linked polyubiquitination of IKBKG/NEMO and subsequent activation of IKBKB/IKKB. In turn, NF-kappa-B is released from NF-kappa-B inhibitors and translocates into the nucleus where it activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. Plays also a role during engagement of the T-cell receptor (TCR) in promoting BCL10 phosphorylation and subsequent NF-kappa-B activation.[1] [2] [3] [4] Publication Abstract from PubMedNOD2 (nucleotide-binding oligomerization domain-containing protein 2) is an internal pattern recognition receptor that recognizes bacterial peptidoglycan and stimulates host immune responses. Dysfunction of NOD2 pathway has been associated with a number of autoinflammatory disorders. To date, direct inhibitors of NOD2 have not been described due to technical challenges of targeting the oligomeric protein complex. Receptor interacting protein kinase 2 (RIPK2) is an intracellular serine/threonine/tyrosine kinase, a key signaling partner, and an obligate kinase for NOD2. As such, RIPK2 represents an attractive target to probe the pathological roles of NOD2 pathway. To search for selective RIPK2 inhibitors, we employed virtual library screening (VLS) and structure based design that eventually led to a potent and selective RIPK2 inhibitor 8 with excellent oral bioavailability, which was used to evaluate the effects of inhibition of RIPK2 in various in vitro assays and ex vivo and in vivo pharmacodynamic models. Identification of Potent and Selective RIPK2 Inhibitors for the Treatment of Inflammatory Diseases.,He X, Da Ros S, Nelson J, Zhu X, Jiang T, Okram B, Jiang S, Michellys PY, Iskandar M, Espinola S, Jia Y, Bursulaya B, Kreusch A, Gao MY, Spraggon G, Baaten J, Clemmer L, Meeusen S, Huang D, Hill R, Nguyen-Tran V, Fathman J, Liu B, Tuntland T, Gordon P, Hollenbeck T, Ng K, Shi J, Bordone L, Liu H ACS Med Chem Lett. 2017 Sep 27;8(10):1048-1053. doi:, 10.1021/acsmedchemlett.7b00258. eCollection 2017 Oct 12. PMID:29057049[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
