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

Amrhein, Jennifer Alisa; Wang, G.; Berger, Benedict‐Tilman; Berger, Lena M.; Kalampaliki, Amalia D.; Krämer, Andreas; Knapp, Stefan; Hanke, Thomas

doi:10.1021/acsmedchemlett.3c00127

Cited by 7 publications

(9 citation statements)

References 34 publications

(64 reference statements)

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“…The detected G2M arrest at high compound concentration (10 μM), but not at 1 μM, may be due to inhibition of these off-targets. Macrocyclization is an excellent method achieving high kinome-wide selectivity which we and others demonstrated on several examples, 24,41–43 including exclusive selectivity for oncogenic mutants over the wild-type protein. 44 The kinome-wide selectivity we achieved for JA310 ( 21c ) is remarkable compared with the promiscuous lead compound 1 used as starting point.…”

Section: Discussionmentioning

confidence: 91%

Synthesis of pyrazole-based macrocycles leads to a highly selective inhibitor for MST3

Amrhein,

Berger,

Balourdas

et al. 2023

Preprint

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MST1, MST2, MST3, MST4, and YSK1 are conserved members of the mammalian sterile 20 kinase (MST) family. MSTs regulate key cellular functions such as cell proliferation, cell migration, metabolic regulation, and cell polarity. The MST3 isozyme plays a role in regulation of cell growth, autophagy and apoptosis, and its dysregulation has been linked to the occurrence of high-grade tumors with poor survival prognosis. To date, there are no isoform-selective inhibitors available that could be used for validating the role of MST3 in tumorigenesis and to assess its potential as an anti-cancer target for drug development. To this end, we have designed a new series of 3-aminopyrazole-based macrocycles based on the structure of an acyclic promiscuous kinase inhibitor. By varying moieties targeting the solvent-exposed region and optimizing the linker, macrocycle JA310 (21c) was synthesized. JA310 exhibited high cellular potency for MST3 with an EC50 = 106 nM and excellent kinome-wide selectivity with significantly lower cellular activity on the closely related kinase MST4 (EC50 = 1.4 uM). The high-resolution crystal structure of the MST3-JA310 complex provided intriguing insights into the distinct binding mode of the macrocycle, which was associated with large-scale structural rearrangements, including concerted induced-fit movements of the glycine-rich loop, the alphaC helix, and the activation loop. In summary, the developed macrocyclic MST3 inhibitor, JA310, demonstrates the utility of macrocyclization for the design of highly selective inhibitors and presents a first chemical probe for MST3.

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Section: Discussionmentioning

confidence: 91%

Synthesis of pyrazole-based macrocycles leads to a highly selective inhibitor for MST3

Amrhein,

Berger,

Balourdas

et al. 2023

Preprint

Self Cite

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“…These hallmarks include sustaining proliferative signaling, deregulating cellular energetics, evading growth suppressors, and resisting cell death. Recent data showed that macrocycles also can target bone morphogenetic protein receptor type‐II (BMPR2) 67 and death‐associated protein kinase 1 (DRAK1) 68 for cancer therapy (Table 2). Therefore, macrocyclic molecules can block nearly 80% of cancer hallmarks to achieve cancer regression.…”

Section: Discussionmentioning

confidence: 99%

Applications of macrocyclic molecules in cancer therapy: Target cancer development or overcome drug resistance

Song,

Wu,

et al. 2023

MedComm – Oncology

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Cancer is a worldwide leading cause of cancer‐related death due to a lack of efficient disease control by drugs. With the increasing unmet needs in cancer treatment, developing novel effective cancer drugs is in great demand. Macrocyclic molecules represent a group of drug molecules with a cyclic skeleton which endows them with unique drug properties such as improved bioavailability, enhanced metabolic stability, increased binding affinity, and favorable pharmacokinetics parameters. The Food and Drug Administration (FDA) has approved a bunch of macrocyclic drugs to treat cancer patients. However, the importance of such molecules in cancer drug development remains underestimated. Recent studies support that macrocyclic molecules can also serve as an effective strategy to overcome drug resistance in cancer treatment, but is a lack of review. The purpose of this manuscript was to provide shreds of evidence on the applications of macrocyclic molecules for cancer therapy: (1) act as cancer drugs to target different proteins critical for cancer development; (2) act as cancer drugs to target resistant mutants of oncogenes to overcome drug resistance in targeted therapy. This review will help to attract more interest in developing macrocyclic drugs for cancer therapy and potentially provide more novel strategies to benefit cancer patients and society.

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“… Chemical structures of BMPR-II inhibitors . The recently disclosed first-in-class BMPR2 (i.e., one of the three type II receptors) inhibitors CDD-1653 and Compound 8a feature a 2,4-diaminopyrimidine core scaffold but are classified as distinct chemotypes based on their putatively different hinge-binding motifs. , …”

Section: Bmp Inhibitorsmentioning

confidence: 99%

“…The latest BMPR2 inhibitor is the macrocyclic pyrazole Compound 8a , which was designed by macrocyclization of a promiscuous, aminopyrazole-based kinase inhibitor . In addition to investigating the BMPR2 affinity (IC 50 = 506 nM), the overall kinome selectivity was assessed and suggested only FLT3 and GSK as relevant off-targets.…”

Section: Bmp Inhibitorsmentioning

confidence: 99%

Small-Molecule Probes as Pharmacological Tools for the Bone Morphogenetic Protein Signaling Pathway

Riege,

Herschel,

Fenkl

et al. 2023

ACS Pharmacol. Transl. Sci.

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The bone morphogenetic protein (BMP) pathway is highly conserved and plays central roles in health and disease. The quality and quantity of its signaling outputs are regulated at multiple levels, offering pharmacological options for targeted modulation. Both target-centric and phenotypic drug discovery (PDD) approaches were applied to identify small-molecule BMP inhibitors and stimulators. In this Review, we accumulated and systematically classified the different reported chemotypes based on their targets as well as modes-of-action, and herein we illustrate the discovery history of selected candidates. A comprehensive summary of available biochemical, cellular, and in vivo activities is provided for the most relevant BMP modulators, along with recommendations on their preferred use as chemical probes to study BMP-related (patho)physiological processes. There are a number of high-quality probes used as BMP inhibitors that potently and selectively interrogate the kinase activities of distinct type I (16 chemotypes available) and type II receptors (3 chemotypes available). In contrast, only a few high-quality BMP stimulator modalities have been introduced to the field due to a lack of profound target knowledge. FK506-derived macrolides such as calcineurin-sparing FKBP12 inhibitors currently represent the best-characterized chemical tools for direct activation of BMP-SMAD signaling at the receptor level. However, several PDD campaigns succeeded in expanding the druggable space of BMP stimulators. Albeit the majority of them do not entirely fulfill the strict chemical probe criteria, many chemotypes exhibit unique and unrecognized mechanisms as pathway potentiators or synergizers, serving as valuable pharmacological tools for BMP perturbation.

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

Cited by 7 publications

References 34 publications

Synthesis of pyrazole-based macrocycles leads to a highly selective inhibitor for MST3

Synthesis of pyrazole-based macrocycles leads to a highly selective inhibitor for MST3

Applications of macrocyclic molecules in cancer therapy: Target cancer development or overcome drug resistance

Small-Molecule Probes as Pharmacological Tools for the Bone Morphogenetic Protein Signaling Pathway

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