Despite their apparent lack of catalytic activity, pseudokinases are essential signaling molecules.Here, we describe the structural and dynamic properties of pseudokinase domains from the Wntbinding receptor tyrosine kinases (PTK7, ROR1, ROR2, RYK), which play important roles in development. We determined structures of all pseudokinase domains in this family, and found that they share a conserved inactive conformation in their activation loop that resembles the autoinhibited insulin receptor kinase (IRK). They also have inaccessible ATP binding pockets, occluded by aromatic residues that mimic a cofactor-bound state. Structural comparisons revealed significant domain plasticity, and alternative interactions that substitute for absent conserved motifs. The pseudokinases also showed strikingly similar dynamic properties to IRK.Despite the inaccessible ATP site, screening identified ATP competitive type-II inhibitors for ROR1. Our results set the stage for an emerging therapeutic modality of "conformational disruptors" to inhibit or modulate non-catalytic functions of pseudokinases deregulated in disease.
Recent studies showed that several pseudokinases from the receptor tyrosine kinase family are important players in regulating cancer cell invasion, metastasis, and drug resistance, suggesting that targeting these proteins can play a therapeutic role in cancer treatment. Receptor Tyr kinase-like orphan receptors (RORs), protein Tyr kinase 7 (PTK7) (also called colon carcinoma kinase 4 (CCK4)), and receptor-like Tyr kinase (RYK) are Wnt ligand binding receptors within the non-canonical Wnt signaling, with important roles in development, tissue homeostasis, and organogenesis. At the cellular level, these receptors transduce signals important for cell survival, migration, polarization, and chemotaxis. Considerable progress has been made in the last decade in the field of pseudokinase signaling, improving our understanding of their structure-function mechanisms, and intracellular network of transduction components. Consequently, their role in various diseases, including cancer, is now scrutinized for therapeutic interventions to improve treatment outcome. In this article, we review findings regarding molecular mechanisms and targeted therapies for ROR1, PTK7, and RYK in hematological malignancies.
Fluorescence‐guided surgery (FGS) is routinely utilized in clinical centers around the world, whereas the combination of FGS and photodynamic therapy (PDT) has yet to reach clinical implementation and remains an active area of translational investigations. Two significant challenges to the clinical translation of PDT for brain cancer are as follows: (1) Limited light penetration depth in brain tissues and (2) Poor selectivity and delivery of the appropriate photosensitizers. To address these shortcomings, we developed nanoliposomal protoporphyrin IX (Nal‐PpIX) and nanoliposomal benzoporphyrin derivative (Nal‐BPD) and then evaluated their photodynamic effects as a function of depth in tissue and light fluence using rat brains. Although red light penetration depth (defined as the depth at which the incident optical energy drops to 1/e, ~37%) is typically a few millimeters in tissues, we demonstrated that the remaining optical energy could induce PDT effects up to 2 cm within brain tissues. Photobleaching and singlet oxygen yield studies between Nal‐BPD and Nal‐PpIX suggest that deep‐tissue PDT (>1 cm) is more effective when using Nal‐BPD. These findings indicate that Nal‐BPD‐PDT is more likely to generate cytotoxic effects deep within the brain and allow for the treatment of brain invading tumor cells centimeters away from the main, resectable tumor mass.
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