Codrug Approach for the Potential Treatment of EML4-ALK Positive Lung Cancer.

We report on the synergistic effect of PI3K inhibition with ALK inhibition for the possible treatment of EML4-ALK positive lung cancer. We have brought together ceritinib (ALK inhibitor) and pictilisib (PI3K inhibitor) into a single bivalent molecule (a codrug) with the aim of designing a molecule for slow release drug delivery that targets EML4-ALK positive lung cancer. We have joined the two drugs through a new, pH-sensitive linker where the resulting codrugs are hydrolytically stable at lower pH (pH 6.

Class 1 PI3K Clinical Candidates and Recent Inhibitor Design Strategies: A Medicinal Chemistry Perspective.

Phosphatidylinositol 3-kinases (PI3Ks) are a family of lipid kinases that phosphorylate the 3-OH of the inositol ring of phosphoinositides, and deregulation of this pathway has implications in many diseases. The search for novel PI3K inhibitors has been at the forefront of academic and industrial medicinal chemistry with over 600 medicinal chemistry-based publications and patents appearing to date, leading to 38 clinical candidates and the launch of two drugs, idelalisib in 2014 and copanlisib in 2017. This Perspective will discuss medicinal chemistry design approaches to novel isoform-selective inhibitors through consideration of brief case histories of compounds that have progressed into clinical development or that have revealed new structural motifs in this highly competitive area of research.

Lipophilic activated ester prodrug approach for drug delivery to the intestinal lymphatic system.

The intestinal lymphatic system plays an important role in the pathophysiology of multiple diseases including lymphomas, cancer metastasis, autoimmune diseases, and human immunodeficiency virus (HIV) infection. It is thus an important compartment for delivery of drugs in order to treat diseases associated with the lymphatic system. Lipophilic prodrug approaches have been used in the past to take advantage of the intestinal lymphatic transport processes to deliver drugs to the intestinal lymphatics.

Design and Elaboration of a Tractable Tricyclic Scaffold To Synthesize Druglike Inhibitors of Dipeptidyl Peptidase-4 (DPP-4), Antagonists of the C-C Chemokine Receptor Type 5 (CCR5), and Highly Potent and Selective Phosphoinositol-3 Kinase δ (PI3Kδ) Inhibitors.

A novel molecular scaffold has been synthesized, and its incorporation into new analogues of biologically active molecules across multiple target classes will be discussed. In these studies, we have shown use of the tricyclic scaffold to synthesize potent inhibitors of the serine peptidase DPP-4, antagonists of the CCR5 receptor, and highly potent and selective PI3K δ isoform inhibitors. We also describe the predicted physicochemical properties of the resulting inhibitors and conclude that the tractable molecular scaffold could have potential application in future drug discovery programs.