Oncogenic conversion of the RET (rearranged during transfection) tyrosine kinase is associated with several cancers. A fragment-based chemical screen lead to the identification of a novel RET inhibitor, Pz-1. Modeling and kinetic analysis identified Pz-1 as a Type-II tyrosine kinase inhibitor, able to bind the DFG-out conformation of the kinase. Importantly, from a single-agent polypharmacology standpoint, Pz-1 was shown active on VEGFR2, which can block blood supply required for RET-stimulated growth. In cell based assays, 1.0 nM of Pz-1 strongly inhibited phosphorylation of all tested RET oncoproteins. At 1.0 mg/kg/day per os, Pz-1 abrogated formation of tumors induced by RET-mutant fibroblasts and blocked phosphorylation of both RET and VEGFR2 in tumor tissue. Pz-1 featured no detectable toxicity up to 100.0 mg/kg, which indicated a large therapeutic window. This study validates the effectiveness and usefulness of a medicinal chemistry polypharmacology approach to obtain an inhibitor capable of targeting multiple oncogenic pathways

Oncogenic conversion of the RET (rearranged during transfection) tyrosine kinase is associated with several cancers. A fragment-based chemical screen lead to the identification of a novel RET inhibitor, Pz-1. Modeling and kinetic analysis identified Pz-1 as a Type-II tyrosine kinase inhibitor, able to bind the DFG-out conformation of the kinase. Importantly, from a single-agent polypharmacology standpoint, Pz-1 was shown active on VEGFR2, which can block blood supply required for RET-stimulated growth. In cell based assays, 1.0 nM of Pz-1 strongly inhibited phosphorylation of all tested RET oncoproteins. At 1.0 mg/kg/day per os, Pz-1 abrogated formation of tumors induced by RET-mutant fibroblasts and blocked phosphorylation of both RET and VEGFR2 in tumor tissue. Pz-1 featured no detectable toxicity up to 100.0 mg/kg, which indicated a large therapeutic window. This study validates the effectiveness and usefulness of a medicinal chemistry polypharmacology approach to obtain an inhibitor capable of targeting multiple oncogenic pathways HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptGoals of targeted treatments are to provide cancer patients with agents, such as tyrosine kinase inhibitors (TKI), designed to target tumor cells or the tumor micro-environment. Unfortunately, drug resistance with TKIs invariably develops due to an inability to sustainably knock out tumor-survival pathways or to maintain activity on the target as additional mutations form. [1][2][3] Resistance can be reduced by identifying, through medicinal chemistry polypharmacology [4] (MCP), personalized TKIs with optimized inhibitory profiles for critical disease-promoting kinases, including crucial mutant targets. A single agent with an appropriate inhibitory profile can possess the benefits of combination therapy and effectively target tumor growth while preventing resistance formation. [5] Herein, we have applied MCP using a novel fragment-based approach to identify a pan-RET/VEGFR2 dual inhibitor. The inhibitor is capable of effectively treating both parenchyma (RET) and stroma (VEGFR2) of RET-driven tumors, while maintaining activity on all tested RET oncogene mutants RET is a transmembrane tyrosine kinase (TK) receptor that has emerged as a molecular target for the treatment of several cancer types, primarily medullary thyroid carcinoma (MTC). [6][7][8] In a tumor environment, VEGFR2-mediated angiogenesis provides oxygen and nutrients necessary for RET oncogenic signaling. Vandetanib (Caprelsa®) and cabozantinib (Cometriq®) were originally discovered as VEGFR2 inhibitors and have been approved to treat MTC, based on their capability to prolong progression-free survival compared to placebo. [9][10] Both agents possess activity on wild type and oncogenic RET mutants, but not on RET gatekeeper (V804) mutants. Therefore, our goal was to implement the concept of single-agent polypharmacology (SAP) in order to design a RET/VEGFR2 dual inhibitor selective and equipotent on both kinases, including...

Die hemmendenen Wirkung eines neuen Inhibitors wurden sorgsam ausgewogen, damit er gegenüber der RET‐Kinase und VEGFR2 gleichermaßen aktiv ist. In der Zuschrift auf beschreiben H.‐y. Li, M. Santoro et al. die Optimierung des dualen Inhibitors für die Behandlung von RET‐getriebenen Tumoren durch einen medizinisch/polypharmakologischen Ansatz. Der Inhibitor therapiert bei gleicher therapeutischer Dosis gleichzeitig das Parenchym (RET) und das Stroma (VEGFR2).

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