CDK inhibitors from past to present: A new wave of cancer therapy

Mughal, Muhammad Jameel; Bhadresha, Kinjal; Kwok, Hang Fai

doi:10.1016/j.semcancer.2022.12.006

Cited by 32 publications

(24 citation statements)

References 112 publications

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Section: Clinical Explanation For Cdk4/6 Inhibitors Selectionmentioning

confidence: 99%

“…50 Here are mentioned only the most prominent clinical trials that validate and analyze the clinical benefits of CDK4/6 inhibitors, while thorough analysis of the latest advancements of these medications has been revised recently. 51 Most common AEs of CDK4/6 inhibitors CDK4/6 inhibitors are generally well-tolerated agents from a safety perspective, with comparable safety profiles. However, there are variations in the occurrence and frequency of toxicities among them, which may impact the selection of a specific medication.…”

Section: Therapeutic Advances Inmentioning

confidence: 99%

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CDK4/6 inhibitors: basics, pros, and major cons in breast cancer treatment with specific regard to cardiotoxicity – a narrative review

Pavlovic,

Niciforovic,

Papic

et al. 2023

Ther Adv Med Oncol

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Breast cancer is characterized by the uncontrolled proliferation of breast cells, with a high incidence reported in 2020 to have affected over 2 million women. In recent years, the conventional methods of treating breast cancer have involved radiotherapy and chemotherapy. However, the emergence of CDK4/6 inhibitors has shown potential as a promising cancer therapy. Cyclin-dependent kinases (CDK) inhibitors are a class of molecules that impede the formation of an active kinase complex, thereby hindering its activity and consequently halting the progression of the cell cycle. It was discovered that they have a significant impact on impeding the progression of the cancer. This is evident with the Food and Drug Administration’s approval of drugs such as palbociclib, ribociclib, and abemaciclib for hormone receptor-positive metastatic breast cancer in combination with specific endocrine therapies. In spite of enormous success in breast cancer treatment, certain obstacles have emerged, such as therapy resistance, side effects, and most of all, cardiotoxicity. Some of these drawbacks have been successfully overcome by dosage reduction, different combinations of the drugs, and the assessment of each patient’s condition and suitability prior to treatment. Yet other drawbacks still require tenacious research, especially certain cases of cardiotoxicities. This article delves into the biological mechanisms of CDK4/6 in the cell cycle and cancer, as well as the clinical advantages and most common adverse events (AEs) associated with CDK4/6 inhibitors. The primary objective of this review is to provide a comprehensive analysis of cardiotoxic AEs and elucidate the underlying pathophysiological mechanisms responsible for the cardiotoxicity of CDK4/6 inhibitors.

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Section: Clinical Explanation For Cdk4/6 Inhibitors Selectionmentioning

confidence: 99%

Section: Therapeutic Advances Inmentioning

confidence: 99%

CDK4/6 inhibitors: basics, pros, and major cons in breast cancer treatment with specific regard to cardiotoxicity – a narrative review

Pavlovic,

Niciforovic,

Papic

et al. 2023

Ther Adv Med Oncol

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“…9,10 Cyclin-dependent kinase (CDK) belongs to the protein phosphorylation enzyme family that catalyzes protein phosphorylation during cell cycle progress and transcriptional command. 11,12 One of the primary characteristics of cancer cells is uncontrollable proliferation. Dysregulated CDK plays a direct or indirect role in the uncontrollable proliferation of cancer cells.…”

Section: ■ Introductionmentioning

confidence: 99%

“…12,15−17 However, consistent toxicity signals, a lack of prognostic biomarkers, and resistance are the key barriers to the ongoing development of these inhibitors. 12 Induction of multiple modes of cell death is a promising therapeutic approach for cancers, and developing dual-target inhibitors is an effective strategy to achieve this goal. 18,19 Drug resistance is a common occurrence in cancer cells, and the high mesenchymal state in cancer cells is thought to be associated with resistance to multiple cancer therapies.…”

Section: ■ Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation for First GPX4 and CDK Dual Inhibitors

Zhu,

Cai,

Kong

et al. 2024

J. Med. Chem.

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The coexistence of ferroptosis and other modes of death has great advantages in the treatment of cancers. A series of glutathione peroxidase 4 (GPX4) and cyclin-dependent kinase (CDK) dual inhibitors were designed and synthesized, given the synergistic anticancer effect of ML162 (GPX4 inhibitor) in combination with indirubin-3′-oxime (IO) (CDK inhibitor).Compound B9 exhibited the highest potential cytotoxic activity against all four cell lines and displayed excellent inhibitory activity against GPX4 (IC 50 = 542.5 ± 0.9 nM) and selective inhibition of CDK 4/6 (IC 50 = 191.2 ± 8.7, 68.1 ± 1.4 nM). Mechanism research showed that B9 could simultaneously induce ferroptosis and arrest cells at the G1 phase in both MDA-MB-231 cells and HCT-116 cells. Compared with ML162 and IO, B9 showed much stronger cancer cell growth inhibition in vivo. These results proved that developing potent GPX4/CDK dual inhibitors is a promising strategy for the malignant cancer therapy.

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“…Intriguingly, some members of this last generation (e.g. palbociclib, ribociclib, abemaciclib and trilaciclib) were FDA approved for first-or second-line treatments of patients with hormone receptor-positive, advanced or metastatic breast cancer and lung cancer [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Dinaciclib synergizes with BH3 mimetics targeting BCL‐2 and BCL‐X_L in multiple myeloma cell lines partially dependent on MCL‐1 and in plasma cells from patients

Beltrán‐Visiedo,

Jiménez‐Alduán,

Díez

et al. 2023

Molecular Oncology

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A better understanding of multiple myeloma (MM) biology has led to the development of novel therapies. However, MM is still an incurable disease and new pharmacological strategies are needed. Dinaciclib, a multiple cyclin‐dependent kinase (CDK) inhibitor, which inhibits CDK1, 2, 5 and 9, displays significant anti‐myeloma activity as found in Phase II clinical trials. In the present work, we have explored the mechanism of dinaciclib‐induced death and evaluated its enhancement by different BH3 mimetics in MM cell lines as well as in plasma cells from MM patients. Our results indicate a synergistic effect of dinaciclib‐based combinations with B‐cell lymphoma 2 (BCL‐2) or B‐cell lymphoma extra‐large (BCL‐XL) inhibitors, especially in MM cell lines with partial dependence on myeloid cell leukemia sequence 1 (MCL‐1). Simultaneous treatment with dinaciclib and BH3 mimetics ABT‐199 or A‐1155463 additionally showed a synergistic effect in plasma cells from MM patients, ex vivo. Altered MM cytogenetics did not affect dinaciclib response ex vivo, alone or in combined treatment, suggesting that these combinations could be a suitable therapeutic option for patients bearing cytogenetic alterations and poor prognosis. This work also opens the possibility to explore cyclin‐dependent kinase 9 (CDK9) inhibition as a targeted therapy in MM patients overexpressing or with high dependence on MCL‐1.

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CDK inhibitors from past to present: A new wave of cancer therapy

Cited by 32 publications

References 112 publications

CDK4/6 inhibitors: basics, pros, and major cons in breast cancer treatment with specific regard to cardiotoxicity – a narrative review

CDK4/6 inhibitors: basics, pros, and major cons in breast cancer treatment with specific regard to cardiotoxicity – a narrative review

Design, Synthesis, and Biological Evaluation for First GPX4 and CDK Dual Inhibitors

Dinaciclib synergizes with BH3 mimetics targeting BCL‐2 and BCL‐X_L in multiple myeloma cell lines partially dependent on MCL‐1 and in plasma cells from patients

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CDK inhibitors from past to present: A new wave of cancer therapy

Cited by 32 publications

References 112 publications

CDK4/6 inhibitors: basics, pros, and major cons in breast cancer treatment with specific regard to cardiotoxicity – a narrative review

CDK4/6 inhibitors: basics, pros, and major cons in breast cancer treatment with specific regard to cardiotoxicity – a narrative review

Design, Synthesis, and Biological Evaluation for First GPX4 and CDK Dual Inhibitors

Dinaciclib synergizes with BH3 mimetics targeting BCL‐2 and BCL‐XL in multiple myeloma cell lines partially dependent on MCL‐1 and in plasma cells from patients

Contact Info

Product

Resources

About

Dinaciclib synergizes with BH3 mimetics targeting BCL‐2 and BCL‐X_L in multiple myeloma cell lines partially dependent on MCL‐1 and in plasma cells from patients