From Structure Modification to Drug Launch: A Systematic Review of the Ongoing Development of Cyclin-Dependent Kinase Inhibitors for Multiple Cancer Therapy

Shi, Zhenfeng; Tian, Lei; Tang, Qiang; Li, Jingyi; Xing, Yue; Ren, Xiaodong; Liu, Chang; Liang, Chengyuan

doi:10.1021/acs.jmedchem.1c02064

“…Increasing the number of animals and assessing the overall survival upon treatment will be important, specifically if this pipeline is utilized for understanding the mechanism of resistance to bacterial therapeutics. Nevertheless, our approach addresses an impediment to the development of new combination therapies for solid tumors -namely, the narrow therapeutic window before significant systemic toxicity is observed [20][21][22] . As the toxins by themselves are not selectively detrimental to the cancer cells, selective delivery of the toxin by the live bacteria in the tumor is crucial to avoid systemic toxicity.…”

Section: Discussionmentioning

confidence: 99%

Design of combination therapy for engineered bacterial therapeutics in non-small cell lung cancer

Deb

¹

,

Wu

²

,

Coker

³

et al. 2022

Sci Rep

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Synthetic biology enables the engineering of bacteria to safely deliver potent payloads to tumors for effective anti-cancer therapies. However, a central challenge for translation is determining ideal bacterial therapy candidates for specific cancers and integrating them with other drug treatment strategies to maximize efficacy. To address this, we designed a screening and evaluation pipeline for characterization of bacterial therapies in lung cancer models. We screened 10 engineered bacterial toxins across 6 non-small cell lung cancer patient-derived cell lines and identified theta toxin as a promising therapeutic candidate. Using a bacteria-spheroid co-culture system (BSCC), analysis of differentially expressed transcripts and gene set enrichment revealed significant changes in at least 10 signaling pathways with bacteria-producing theta toxin. We assessed combinatorial treatment of small molecule pharmaceutical inhibitors targeting 5 signaling molecules and of 2 chemotherapy drugs along with bacterially-produced theta toxin and showed improved dose-dependent response. This combination strategy was further tested and confirmed, with AKT signaling as an example, in a mouse model of lung cancer. In summary, we developed a pipeline to rapidly characterize bacterial therapies and integrate them with current targeted therapies for lung cancer.

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“…The combination with RNA-seq based identi cation of small molecule inhibitors enabled rapid and parallel assays for selection of effective therapies, which were then validated for safety and e cacy in a mouse model. This approach addresses an impediment to the development of new combination therapies for solid tumors -namely, the narrow therapeutic window before signi cant systemic toxicity is observed [20][21][22] . Several species of bacteria can selectively colonize solid tumors, primarily due to reduced immune surveillance in tumor cores, and can be controlled to deliver therapeutic payloads after colonizing tumors 23-25 .…”

Section: Discussionmentioning

confidence: 99%

Design of combination therapy for engineered bacterial therapeutics in non-small cell lung cancer

Deb

¹

,

Wu

²

,

Coker

³

et al. 2022

Preprint

0

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Synthetic biology enables the engineering of bacteria to safely deliver potent payloads to tumors for effective anti-cancer therapies. However, a central challenge for translation is determining ideal bacterial therapy candidates for specific cancers and integrating them with other drug treatment strategies to maximize efficacy. To address this, we designed a screening and evaluation pipeline for characterization of bacterial therapies in lung cancer models. We screened 10 engineered bacterial toxins across 6 non-small cell lung cancer patient-derived cell lines and identified theta toxin as a promising therapeutic candidate. Using a bacteria-spheroid co-culture system (BSCC), analysis of differentially expressed transcripts and gene set enrichment revealed significant changes in at least 10 signaling pathways with bacteria-producing theta toxin. We assessed combinatorial treatment of small molecule pharmaceutical inhibitors targeting 5 signaling molecules and of 2 chemotherapy drugs along with bacterially-produced theta toxin and showed improved dose-dependent response. This combination strategy was further tested and confirmed, with AKT signaling as an example, in a mouse model of lung cancer. In summary, we developed a pipeline to rapidly characterize bacterial therapies and integrate them with current targeted therapies for lung cancer.

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“…In 2010, Novartis, in collaboration with Astex, reported 3j ( Ribociclib , LEE011 ), an orally active, highly specific CDK4/6 inhibitor with IC 50 values of 10 and 39 nM, respectively [ 60 , 61 ]. To the best of our knowledge, the development course of 3j has not been disclosed [ 55 , 62 ]. Given the structural similarity and the chronological order of launch, we assume that 3j was designed with 3i as the lead compound.…”

Section: Indole/azaindole/oxindole-based Approved Atp-competitive Kin...mentioning

confidence: 99%

Approved Small-Molecule ATP-Competitive Kinases Drugs Containing Indole/Azaindole/Oxindole Scaffolds: R&D and Binding Patterns Profiling

Zhang

¹

,

He

²

,

Gao

³

et al. 2023

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Kinases are among the most important families of biomolecules and play an essential role in the regulation of cell proliferation, apoptosis, metabolism, and other critical physiological processes. The dysregulation and gene mutation of kinases are linked to the occurrence and development of various human diseases, especially cancer. As a result, a growing number of small-molecule drugs based on kinase targets are being successfully developed and approved for the treatment of many diseases. The indole/azaindole/oxindole moieties are important key pharmacophores of many bioactive compounds and are generally used as excellent scaffolds for drug discovery in medicinal chemistry. To date, 30 ATP-competitive kinase inhibitors bearing the indole/azaindole/oxindole scaffold have been approved for the treatment of diseases. Herein, we summarize their research and development (R&D) process and describe their binding models to the ATP-binding sites of the target kinases. Moreover, we discuss the significant role of the indole/azaindole/oxindole skeletons in the interaction of their parent drug and target kinases, providing new medicinal chemistry inspiration and ideas for the subsequent development and optimization of kinase inhibitors.

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From Structure Modification to Drug Launch: A Systematic Review of the Ongoing Development of Cyclin-Dependent Kinase Inhibitors for Multiple Cancer Therapy

Cited by 35 publications

References 209 publications

Design of combination therapy for engineered bacterial therapeutics in non-small cell lung cancer

Design of combination therapy for engineered bacterial therapeutics in non-small cell lung cancer

Design of combination therapy for engineered bacterial therapeutics in non-small cell lung cancer

Approved Small-Molecule ATP-Competitive Kinases Drugs Containing Indole/Azaindole/Oxindole Scaffolds: R&D and Binding Patterns Profiling

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