Design and Synthesis of 5-Aryl-pyridone-carboxamides as Inhibitors of Anaplastic Lymphoma Kinase

Abstract

Anaplastic lymphoma kinase (ALK) is a promising new target for therapy of certain cancers such as anaplastic large-cell lymphoma (ALCL) and inflammatory myofibroblastic tumor (IMT). We have identified a series of novel pyridones as kinase inhibitors of ALK by application of a stepwise process involving in vitro screening of a novel targeted library followed by iterative template modification based on medicinal chemistry insights and computational ranking of virtual libraries. Using this process, we discovered ALK-selective inhibitors with improved potency and selectivity. Herein the details of the design process and synthesis of these novel pyridones, along with their enzymatic and cell-based activity, are discussed.

Development of anaplastic lymphoma kinase (ALK) small‐molecule inhibitors for cancer therapy

“…SARs of this compound and closely related analogues were detailed in a 2006 publication that describes these investigations. 268 This first-generation series of compounds also possessed inhibitory activity against ALCL cell line proliferation in vitro, although the activity was non-selective compared to control cells and was modest, with cellular IC 50 values in the 4-18 mM range.…”

“…266 Several reports appeared in the medical literature in 2006 that have further validated the anti-tumor efficacy of ALK inhibition; these reports describe small-molecule inhibitors that exhibit more substantial anti-ALK potency and selectivity (among other examples to be described in detail in the following section, see Refs. 246,248,[267][268][269], unlike some of the agents noted immediately above.…”

“…Since no crystal structures of ALK are available, the group chose to use homology modeling to assist evaluation of the novel scaffolds, rank virtual libraries, and perform docking studies. 268 Since the initial combination of molecular structural determination together with computation as an important emerging tool for drug development and its application to acquired immunodeficiency syndrome (AIDS) and bacterial drug resistance issues, 316 docking and scoring technologies have been widely utilized at different stages of the drug discovery process. Among the three main challenges of (1) predicting the binding mode of a known active ligand, (2) predicting the binding affinities of related compounds from a known active series, and (3) identifying new ligands using virtual screening, prediction of the mode of ligand binding in the active site of a protein is the most straightforward and is the application in which most success has been achieved.…”

Mass Spectrometry-based Proteomic Studies of Human Anaplastic Large Cell Lymphoma

“…Although studies have assessed inhibition of ALK by both small interfering RNA (73), short hairpin RNA (74), tyrosine kinase inhibitors (75), and more recently small molecule inhibitors with selective activity against ALK (76,77), the proteomic effects of these agents have yet to be evaluated. By determining changes in protein expression in response to the specific inhibition of ALK, we may uncover novel proteins required for NPM/ALK survival as well as discover potential therapeutic targets that may be used in combination with ALK inhibitors.…”

FeCI3‐promoted [3+3] cycloaddition: Efficient preparation of 1,2‐dihydro‐2‐oxo‐3‐pyridinecarboxylate and 1,2‐dihydro‐2‐oxo‐3‐pyridinecarboxamide derivatives

“…In summary, a novel approach was developed for the preparation of 1,2-dihydro-2-oxo-3-pyridinecarboxylates and 1,2-dihydro-2-oxo-3-pyridinecarboxamides, which can be further modified as lead compounds such as cytokine inhibitors [7] and anaplastic lymphoma kinase inhibitors [8]. The [3+3] cycloaddition promoted by FeCl 3 in acid media involves cyclization of Michael adduct amide-ketone and subsequent aromatization, which is supplementary to the existing approaches for the assembly of 2-pyridone derivatives.…”