Development of Small Macrocyclic Kinase Inhibitors

Ma, Jin; Sánchez‐Duffhues, Gonzalo; Caradec, Josselin; Benderitter, Pascal; Hoflack, Jan; Dijke, Peter ten

doi:10.4155/fmc-2021-0342

Cited by 4 publications

(6 citation statements)

References 6 publications

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“…Activin receptor-like kinase-2 (ALK2) is one of the activin receptor-like kinases involved in bone morphogenetic protein (BMP) that has a significant role in biological processes controlling the development of bone, heart, and brain . Several studies have been reported where it was found that macrocyclic inhibitors offered improved physicochemical characteristics and potency. , Therefore, we performed rigid body docking using the apo form of ALK2 and compared the macrocyclic cocrystallized compounds with our GBB-based macrocycles 3b – d . According to the results, van der Waals forces had the highest scoring weight, averaging 16 interactions per molecule.…”

Section: Resultsmentioning

confidence: 99%

“…Macrocycles especially have attracted great interest as kinase inhibitors. − Due to their size, they bind more tightly to the kinase and in a more specific manner; macrocyclic kinase inhibitors have thus emerged as a successful solution to overcome the selectivity issues encountered when targeting this major family, which has over 500 closely related proteins. Additionally, they may be able to bind to allosteric sites on the kinase that are not accessible to small molecules. , …”

Section: Introductionmentioning

confidence: 99%

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Instant Macrocyclizations via Multicomponent Reactions

Fragkiadakis,

Anastasiou,

Zingiridis

et al. 2023

J. Org. Chem.

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Macrocycles fascinate chemists due to both their structure and their applications. However, we still lack efficient and sustainable synthetic methods, giving us straightforward access to them. Herein, a rapid macrocyclization utilizing a two-step, one-pot approach based on orthogonal multicomponent reaction (MCR) tactics is introduced. This synthetic protocol, which is based on Ugi and Groebke–Blackburn–Bienaymé reactions with isocyanides tethered to alkyl tosylates, yields medium sized macrocycles that are otherwise difficult to achieve. Single crystal structures reveal conformational reorganization via intramolecular hydrogen bonding, and modeling studies profile the synthesized libraries.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Instant Macrocyclizations via Multicomponent Reactions

Fragkiadakis,

Anastasiou,

Zingiridis

et al. 2023

J. Org. Chem.

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“…Several clinically approved drugs, such as selective kinase inhibitors, are designed to target and inhibit the enzymatic activity of specific protein kinases. These drugs are employed in the treatment of various conditions, including Alzheimer’s disease, polycystic kidney disease, rheumatoid arthritis, cancer, and numerous others [ 21 ]. FDA-approved protein kinase inhibitors, along with their respective targets, are listed in Figure 1 , which includes acyclic as well as cyclic inhibitors.…”

Section: Introductionmentioning

confidence: 99%

“…Secondly, a high level of specificity is necessary to selectively target the desired kinase while avoiding interference with other kinases within this extensive enzyme family, thereby reducing the risk of side effects. Lastly, these requirements need to be fulfilled while maintaining the physicochemical properties of the designed compounds that are favorable for further development, often referred to as drug-like properties [ 21 ]. Using a macrocyclic strategy in the design of kinase inhibitors presents a compelling and innovative solution to address these challenges.…”

Section: Introductionmentioning

confidence: 99%

An Intriguing Purview on the Design of Macrocyclic Inhibitors for Unexplored Protein Kinases through Their Binding Site Comparison

Bhujbal

Hah

2023

Pharmaceuticals

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Kinases play an important role in regulating various intracellular signaling pathways that control cell proliferation, differentiation, survival, and other cellular processes, and their deregulation causes more than 400 diseases. Consequently, macrocyclization can be considered a noteworthy approach to developing new therapeutic agents for human diseases. Macrocyclization has emerged as an effective drug discovery strategy over the past decade to improve target selectivity and potency of small molecules. Small compounds with linear structures upon macrocyclization can lead to changes in their physicochemical and biological properties by firmly reducing conformational flexibility. A number of distinct protein kinases exhibit similar binding sites. Comparison of protein binding sites provides crucial insights for drug discovery and development. Binding site similarities are helpful in understanding polypharmacology, identifying potential off-targets, and repurposing known drugs. In this review, we focused on comparing the binding sites of those kinases for which macrocyclic inhibitors are available/studied so far. Furthermore, we calculated the volume of the binding site pocket for each targeted kinase and then compared it with the binding site pocket of the kinase for which only acyclic inhibitors were designed to date. Our review and analysis of several explored kinases might be useful in targeting new protein kinases for macrocyclic drug discovery.

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“…Similarly, improved blood–brain permeability was observed for the macrocycle lorlatinib compared with the acyclic analogue crizotinib . The increasing number of drug candidates and the numerous publications in recent years have demonstrated that macrocyclization is an efficient strategy to improve the potency, target selectivity, as well as biochemical properties and offers a great opportunity for the discovery of new drugs. ,− …”

mentioning

confidence: 99%

Design and Synthesis of Pyrazole-Based Macrocyclic Kinase Inhibitors Targeting BMPR2

Amrhein

Wang

Berger

et al. 2023

ACS Med. Chem. Lett.

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Bone morphogenetic protein (BMP) signaling is mediated by transmembrane protein kinases that form heterotetramers consisting of type-I and type-II receptors. Upon BMP binding, the constitutively active type-II receptors activate specific type-I receptors by transphosphorylation, resulting in the phosphorylation of SMAD effector proteins. Drug discovery in the receptor tyrosine kinase-like (TKL) family has largely focused on type-I receptors, with few inhibitors that have been published targeting type-II receptors. BMPR2 is involved in several diseases, most notably pulmonary arterial hypertension, but also contributes to Alzheimer's disease and cancer. Here, we report that macrocyclization of the promiscuous inhibitor 1, based on a 3amino-1H-pyrazole hinge binding moiety, led to a selective and potent BMPR2 inhibitor 8a.

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Development of Small Macrocyclic Kinase Inhibitors

Cited by 4 publications

References 6 publications

Instant Macrocyclizations via Multicomponent Reactions

Instant Macrocyclizations via Multicomponent Reactions

An Intriguing Purview on the Design of Macrocyclic Inhibitors for Unexplored Protein Kinases through Their Binding Site Comparison

Design and Synthesis of Pyrazole-Based Macrocyclic Kinase Inhibitors Targeting BMPR2

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