B483 A Novel Small-Molecule Inhibitor RGB 286638 Induces Apoptosis and Necrosis in Multiple Myeloma

Progression of the cell cycle is controlled by various activating and inhibiting cellular factors. The subtle balance between these counteracting regulators in normal cells ensures proper cell cycle progression and facilitates cellular responses to a variety of stress stimuli. Key activators include cyclin-dependent kinases (CDKs) and, consequently, loss or inactivation of CDK inhibitors contributes to the escape of cancer cells from cell cycle control and hyperactivation of CDKs occurs in various neurodegenerative disorders. However, these adverse effects may be compensated by pharmacological counterparts. Inhibitors of CDKs representing various classes of compounds with diverse CDK inhibitory patterns have been developed, but inhibitors that have high selectivity and offer highly targeted activity against both cell cycle and transcriptional CDKs are of particular interest. This review focuses on pharmacological CDK inhibitors that have entered clinical trials and some compounds that have been evaluated preclinically. Recent discoveries in cell cycle regulation have provided rationales for clinical applications of CDK inhibitors in both monotherapeutic and combined therapeutic regimens.

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Novel Potent Pharmacological Cyclin-Dependent Kinase Inhibitors

Węsierska‐Gądek

Chamrád

Kryštof

2009

Future Med. Chem.

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The Impact Of CDK Inhibition In Human Malignancies Associated With Pronounced Defects In Apoptosis: Advantages Of Multi-Targeting Small Molecules

Węsierska‐Gądek

Kramer

2012

Future Med. Chem.

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Malignant cells in chronic lymphocytic leukemia (CLL) and related diseases are heterogeneous and consist primarily of long-lived resting cells in the periphery and a minor subset of dividing cells in proliferating centers. Both cell populations have different molecular signatures that play a major role in determining their sensitivity to therapy. Contemporary approaches to treating CLL are heavily reliant on cytotoxic chemotherapeutics. However, none of the current treatment regimens can be considered curative. Pharmacological CDK inhibitors have extended the repertoire of potential drugs for CLL. Multi-targeted CDK inhibitors affect CDKs involved in regulating both cell cycle progression and transcription. Their interference with transcriptional elongation represses anti-apoptotic proteins and, thus, promotes the induction of apoptosis. Importantly, there is evidence that treatment with CDK inhibitors can overcome resistance to therapy. The pharmacological CDK inhibitors have great potential for use in combination with other therapeutics and represent promising tools for the development of new curative treatments for CLL.

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B483 A Novel Small-Molecule Inhibitor RGB 286638 Induces Apoptosis and Necrosis in Multiple Myeloma

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Novel Potent Pharmacological Cyclin-Dependent Kinase Inhibitors

Novel Potent Pharmacological Cyclin-Dependent Kinase Inhibitors

The Impact Of CDK Inhibition In Human Malignancies Associated With Pronounced Defects In Apoptosis: Advantages Of Multi-Targeting Small Molecules

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