Current therapies for chronic pain can have insufficient efficacy and lead to side effects, necessitating research of novel targets against pain. Although originally identified as an oncogene, Tropomyosinrelated kinase A (TrkA) is linked to pain and elevated levels of NGF (the ligand for TrkA) are associated with chronic pain. Antibodies that block TrkA interaction with its ligand, NGF, are in clinical trials for pain relief. Here, we describe the identification of TrkA-specific inhibitors and the structural basis for their selectivity over other Trk family kinases. The X-ray structures reveal a binding site outside the kinase active site that uses residues from the kinase domain and the juxtamembrane region. Three modes of binding with the juxtamembrane region are characterized through a series of ligand-bound complexes. The structures indicate a critical pharmacophore on the compounds that leads to the distinct binding modes. The mode of interaction can allow TrkA selectivity over TrkB and TrkC or promiscuous, pan-Trk inhibition. This finding highlights the difficulty in characterizing the structure-activity relationship of a chemical series in the absence of structural information because of substantial differences in the interacting residues. These structures illustrate the flexibility of binding to sequences outside of-but adjacent to-the kinase domain of TrkA. This knowledge allows development of compounds with specificity for TrkA or the family of Trk proteins.TrkA | kinase | pain | inhibition | selectivity
Fibroblast activation protein-α (FAP) is a type II integral serine protease that is specifically expressed by activated fibroblasts. Cancer-associated fibroblasts (CAFs) in the tumor stroma have an abundant and stable expression of FAP, which plays an important role in promoting tumor growth, invasion, metastasis, and immunosuppression. For example, in females with a high incidence of breast cancer, CAFs account for 50–70% of the cells in the tumor’s microenvironment. CAF overexpression of FAP promotes tumor development and metastasis by influencing extracellular matrix remodeling, intracellular signaling, angiogenesis, epithelial-to-mesenchymal transition, and immunosuppression. This review discusses the basic biological characteristics of FAP and its applications in the diagnosis and treatment of various cancers. We review the emerging basic and clinical research data regarding the use of nanomaterials that target FAP.
Following Dexter & Agol (2009) we present a new public code for the fast calculation of null geodesics in the Kerr spacetime. Using Weierstrass' and Jacobi's elliptic functions, we express all coordinates and affine parameters as analytical and numerical functions of a parameter p, which is an integral value along the geodesic. This is a main difference of our code compares with previous similar ones. The advantage of this treatment is that the information about the turning points do not need to be specified in advance by the user, and many applications such as imaging, the calculation of line profiles or the observer-emitter problem, etc become root finding problems. All elliptic integrations are computed by Carlson's elliptic integral method as Dexter & Agol (2009) did, which guarantees the fast computational speed of our code. The formulae to compute the constants of motion given by Cunningham & Bardeen (1973) have been extended, which allow one readily to handle the situations, in which the emitter or the observer has arbitrary distance and motion state with respect to the central compact object. The validation of the code has been extensively tested by its application to toy problems from the literature. The source FORTRAN code is freely available for download on the web. 1
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