6d20

Crystal structure of Tyrosine-protein kinase receptor in complex with 5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4(3H)-one and 5-{[2,4-dichloro-5-(pyridin-2-yl)benzene-1-carbonyl]amino}-N-(2-hydroxy-2-methylpropyl)-1-phenyl-1H-pyrazole-3-carboxamide InhibitorsCrystal structure of Tyrosine-protein kinase receptor in complex with 5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4(3H)-one and 5-{[2,4-dichloro-5-(pyridin-2-yl)benzene-1-carbonyl]amino}-N-(2-hydroxy-2-methylpropyl)-1-phenyl-1H-pyrazole-3-carboxamide Inhibitors

Structural highlights 6d20 is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: , Related: 6d1y, 6d1z Activity: Receptor protein-tyrosine kinase, with EC number 2.7.10.1 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [NTRK1_HUMAN] Defects in NTRK1 are a cause of congenital insensitivity to pain with anhidrosis (CIPA) [MIM:256800]. CIPA is characterized by a congenital insensitivity to pain, anhidrosis (absence of sweating), absence of reaction to noxious stimuli, self-mutilating behavior, and mental retardation. This rare autosomal recessive disorder is also known as congenital sensory neuropathy with anhidrosis or hereditary sensory and autonomic neuropathy type IV or familial dysautonomia type II. Defects in NTRK1 are a cause of thyroid papillary carcinoma (TPC) [MIM:188550]. TPC is a common tumor of the thyroid that typically arises as an irregular, solid or cystic mass from otherwise normal thyroid tissue. Papillary carcinomas are malignant neoplasm characterized by the formation of numerous, irregular, finger-like projections of fibrous stroma that is covered with a surface layer of neoplastic epithelial cells. Note=Chromosomal aberrations involving NTRK1 are found in thyroid papillary carcinomas. Translocation t(1;3)(q21;q11) with TFG generates the TRKT3 (TRK-T3) transcript by fusing TFG to the 3'-end of NTRK1; a rearrangement with TPM3 generates the TRK transcript by fusing TPM3 to the 3'-end of NTRK1; an intrachromosomal rearrangement that links the protein kinase domain of NTRK1 to the 5'-end of the TPR gene forms the fusion protein TRK-T1. TRK-T1 is a 55 kDa protein reacting with antibodies against the C-terminus of the NTRK1 protein. Function [NTRK1_HUMAN] Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympathetic and nervous neurons. High affinity receptor for NGF which is its primary ligand, it can also bind and be activated by NTF3/neurotrophin-3. However, NTF3 only supports axonal extension through NTRK1 but has no effect on neuron survival. Upon dimeric NGF ligand-binding, undergoes homodimerization, autophosphorylation and activation. Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades driving cell survival and differentiation. Through SHC1 and FRS2 activates a GRB2-Ras-MAPK cascade that regulates cell differentiation and survival. Through PLCG1 controls NF-Kappa-B activation and the transcription of genes involved in cell survival. Through SHC1 and SH2B1 controls a Ras-PI3 kinase-AKT1 signaling cascade that is also regulating survival. In absence of ligand and activation, may promote cell death, making the survival of neurons dependent on trophic factors. Isoform TrkA-III is resistant to NGF, constitutively activates AKT1 and NF-kappa-B and is unable to activate the Ras-MAPK signaling cascade. Antagonizes the anti-proliferative NGF-NTRK1 signaling that promotes neuronal precursors differentiation. Isoform TrkA-III promotes angiogenesis and has oncogenic activity when overexpressed. Publication Abstract from PubMed Tropomyosin receptor kinases are a family of three tyrosine kinases (TrkA, TrkB, TrkC) activated by peptide hormones of the neurotrophin family: nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) and neurotrophin 4 (NT4). The NGF antibody tanezumab has provided clinical proof of concept for inhibition of the TrkA kinase pathway in pain. In turn, this has led to significant interest in the development of small molecule inhibitors of TrkA as an alternative intervention point on the NGF pathway. However, recent reports have demonstrated the challenge of achieving TrkA subtype selectivity over TrkB and TrkC via a Type I and Type II inhibitor binding mode. In this case Type III or Type IV allosteric inhibitors present a more promising selectivity design approach. In addition to subtype selectivity, TrkA inhibitors with minimal brain availability are required to deliver an appropriate safety profile for chronic, non-life threatening pain indications. Herein we describe the discovery of a highly potent, subtype selective, peripherally restricted, efficacious and well-tolerated series of allosteric TrkA inhibitors. The use of SBDD methodologies such as docking analysis, crystallographic water analysis, and protein-ligand interaction analysis led to the rapid optimization of potency and lipophilic efficiency. Furthermore, introducing P-gp and BCRP efflux transporter activity combined with reducing intestinal metabolism liability allowed for chemical equity having a good absorption profile and culminated in the delivery of candidate quality compound 23. Discovery of Allosteric, Potent, Subtype Selective and Peripherally Restricted TrkA Kinase Inhibitors.,Bagal SK, Omoto K, Blakemore DC, Bungay PJ, Bilsland JG, Clarke PJ, Corbett MS, Cronin CN, Cui JJ, Dias R, Flanagan NJ, Greasley SE, Grimley R, Johnson E, Fengas D, Kitching L, Kraus ML, McAlpine I, Nagata A, Waldron GJ, Warmus JS J Med Chem. 2018 Apr 19. doi: 10.1021/acs.jmedchem.8b00280. PMID:29672039 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

spinqualitylabelsall models 6d20, resolution 1.94Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image