Synthetic Opportunities and Challenges for Macrocyclic Kinase Inhibitors

Abstract

Macrocycles are typically cyclic variants of inhibitors derived from uncyclized canonical molecules or from natural products. For medicinal chemistry, drug-like macrocycles have received increasing interest over the past few years, since it has been demonstrated that macrocyclization can favorably alter the biological and physiochemical properties as well as selectivity in comparison to the acyclic analogue. Recent drug approvals such as Lorlatinib, glecaprevir, or voxilaprevir underline the clinical relevance of drug-like macrocycles. However, the synthesis of drug-like macrocycles can be challenging, since the ring-closing reaction is generally challenging with yields depending on the size and geometry of the bridging linker. Nevertheless, macrocycles are one opportunity to expand the synthetic toolbox for medicinal chemistry to provide bioactive molecules. Therefore, we reviewed the past literature of drug-like macrocycles highlighting reactions that have been successfully used for the macrocyclization. We classified the cyclization reactions by their type, ring-size, yield, and macrocyclization efficiency index.

Frontiers in Medicinal Chemistry 2022 Goes Virtual

“…The first lecture was given by Thomas Hanke (University / Structural Genomic Consortium Frankfurt) who emphasized the power of macrocyclization approaches for the discovery of protein kinase‐targeted chemical probes and drugs. After introducing the opportunities and challenges of macrocycles in the kinase field, macrocyclization reactions and general design strategies for macrocyclic protein kinase inhibitors were discussed [57] . The second part of the talk focused on studies showcasing the development of macrocyclic kinase inhibitors.…”

An overview of kinase downregulators and recent advances in discovery approaches

“…The macrocycles not only offer an opportunity for chemical novelty than the existing scaffolds but also improve the selectivity and overcome the acquired drug resistance. 82 So far, except for the three mTOR inhibitors, only one ALK/ROS1 dual kinase inhibitor lorlatinib has been developed via rational design, which is a third-generation ALK/ROS1 inhibitor and it can overcome gatekeeper and solvent-front mutations. 83 To avoid steric hindrance with a gatekeeper and solvent-front mutations, lorlatinib is designed using a rigid amide-linked 12-membered macrocycle based on the structure of crizotinib.…”

Illuminating the Dark: Highly Selective Inhibition of Serine/Threonine Kinase 17A with Pyrazolo[1,5-a]pyrimidine-Based Macrocycles

“…One possibility to improve and control shape complementarity and to lock a bioactive inhibitor conformation is the introduction of macrocyclization. Macrocyclic kinase inhibitors typically contain an ATP-mimetic pharmacophore, which is constrained by a linker of 12 or more atoms that connects flexible moieties in acyclic conventional inhibitors. , As a result of the conformational restriction, the entropic costs during binding can be reduced, which presumably leads to an increased binding affinity to the target protein . Despite the loss of flexibility, macrocycles are far from being rigid and can therefore also interact with dynamic binding sites in proteins .…”