Table 1.

CDKis generations and features.

	First Generation (e.g., Alvocidib)	Second Generation (e.g., Dinaciclib, CYC065)	Third Generation (e.g., Abemaciclib, Ribociclib, Palbociclib)	Fourth Generation (e.g., TG02)
Mode of action	Multi-serine/threonine CDKis	Inhibitor of a wide range of CDKs	Inhibitor of CDK4 and CDK6	Pyrimidine-based multi-kinase inhibitor (together with JAK2 and FLT3)
Side effects	-Tumour lyses syndrome (in CCL, reversible) -Myelosuppression -Diarrhea	-Neutropenia -Thrombocytopenia -Pneumonia -Sepsis	-Neutropenia -Fatigue -GE toxicity (diarrhea)	-early clinical development, side effects not yet available
Advantages	-First to demonstrate clinical activity in vitro	-activity shown in Multiple Myeloma -Enhance PARPis activity in vitro (Dinaciclib)	-Higher potency -Selective activity intumour cells -Cross BBB (abemaciclib) -Manageable safety profile -oral administration -administered once daily (palbociclib and ribociclib)	-Higher potency (non pan-CDK) -Large spectrum of activity (e.g., also angiogenesis) -Potent anti-proliferative effects in tumour cell lines
Limitations	-Low potency (pan-CDK) -Lack of specificity -Off target toxic effects -intravenous administration	-Non selective activity -Equivalent activity on normal and tumour cells -intravenous administration	-Prolonged QT interval (mandatory ECG before and during treatment with ribociclib)	-Under investigation in preclinical and clinical setting -dose-dependent

Legend: CDK: cyclin-dependent kinase; CCL: chronic lymphocytic leukemia; AML: acute myeloid leukemia; GE: gastro-enteric; BBB: blood brain barrier; JAK2: Janus Kinase 2; FLT3: fms-like tyrosine kinase-3; PARPi: PARP inhibitors.