Table 1.
Inhibitors of cell-cycle proteins in clinical development.
| Drug name (alternative names) | Primary target (IC50) | Off target (IC50) | Clinical trials/clinical utilization | Reference |
|---|---|---|---|---|
| 1st generation (Pan-kinase inhibitors) | ||||
| Flavopiridol (Alvocidib, L86-8275, HMR-1275) | CDK9 (20 nM), CDK1 (30 nM), CDK2 (40 nM), CDK4 (20–40 nM), CDK6 (60 nM) | CDK7 (875 nM), MAPK, PKC, EGFR | 66 phase I or II clinical trials in different malignancies; 5 active trials (MDS/AML); not registered for clinical use in oncology | (Shapiro, 2006) |
| Roscovitine (Seliciclib, CYC202) | CDK5 (0.16 μM), CDK1 (0.65 μM), CDK2 (0.7 μM) | ERK | 3 phase I or II clinical trials in different malignancies; no active trial and no registration for clinical use in oncology | (Ali et al., 2009; Jabbour-Leung et al., 2016) |
| 2nd generation (Multiple-kinase inhibitors) | ||||
| Dinaciclib (SCH727965) | CDK2 (1 nM), CDK5 (1 nM), CDK1 (3 nM), CDK9 (4 nM) | 18 phase I, II and III clinical trials in different malignancies; the only phase 3 trial in CLL (results to be posted); 4 active trials; no registration for clinical use in oncology | (Parry et al., 2010; Ghia et al. 2017) | |
| AT7519 | CDK9 (<10 nM), CDK5 (13 nM), CDK2 (47 nM) | CDK4 (100 nM), CDK6 (170 nM), CDK1 (210 Nm), CDK7 (2400 nM), GSK-3β | 5 phase I or II clinical trials in heamotologic malignancies; 1 active trial; no registration for clinical use in oncology | (Otto and Sicinski, 2017) |
| Milciclib (PHA-848125) | CDK2 (45 nM) | CDK7 (150 nM), CDK4 (160 nM), CDK5 (265 nM), CDK2 (363 nM), CDK1 (398 nM), TrKa | 4 phase I or II clinical trials in thymic and liver carcinomas; 1 active trial; no registration for clinical use in oncology | (Otto and Sicinski, 2017) |
| SB1317 (TG02) | CDK2 (13 nM) | JAK2, FLT3 | 7 phase I or II clinical trials in various solid tumors and hematological malignancies; 3 active trials; no registration for clinical use in oncology | (Otto and Sicinski, 2017) |
| CYC065 | CDK2 (5 nM), CDK9 (26 nM) | 3 phase I active clinical trials in hematological malignancies; no registration for clinical use in oncology | (Otto and Sicinski, 2017) | |
| RGB-286638 | CDK9 (1 nM), CDK1 (2 nM), CDK2 (3 nM), CDK4 (4 nM), CDK3 (5 nM), CDK5 (5 nM) | CDK7 (44 nM), CDK6 (55 nM), GSK-3β, TAK1, JAK2, MEK1 | 1 withdrawn phase I clinical trial | (Otto and Sicinski, 2017) |
| 3rd generation (Specific kinase inhibitors) | ||||
| Palbociclib (PD-0332991, Ibrance) | CDK4 (9–11 nM), CDK6 (15 nM) | registered for clinical use in hormone receptor positive, HeR2-negative advanced breast cancer patients; 215 phase I/II/III/IV clinical trials, including PALOMA series; being tested in various malignancies (173 active) | (Fry et al., 2004) | |
| Ribociclib (LEE011, Kisqali) | CDK4 (10 nM), CDK6 (39 nM) | registered for clinical use in hormone receptor positive, HeR2-negative advanced breast cancer patients; 103 phase I/II/III clinical trials, including MONALEESA series; being tested in various malignancies (72 active) | (Hortobagyi et al., 2016) | |
| Abemaciclib (LY2835219, Verzenio) | CDK4 (2 nM), CDK6 (10 nM) | registered for clinical use in hormone receptor positive, HER2-negative advanced breast cancer patients; 100 phase I/II/III/IV clinical trials, including MONARCH series; being tested in various malignancies (81 active) | (Sledge et al., 2017) | |
| Trilaciclib (G1T28) | CDK4 (1 nM), CDK6 (4 nM) | 4 phase I and II clinical trials in small cell lung cancer and breast cancer; no registration for clinical use in oncology | (Tan et al., 2019) | |
| Lerociclib (G1T38) | CDK4 (1 nM), CDK6 (4 nM) | CDK9 (28 nM), CDK5 (0.8–1.2 μM), CDK2 (1.5–3.6 μM), CDK1 (2.4 μM), CDK7 (2.4 μM) | 3 phase I and II clinical trials in lung and breast cancer; no registration for clinical use in oncology | (Bisi et al., 2017) |
| PHA-767491 (NMS-1116354) | CDC7 (10 nM), CDK9 (34 nM) | CDK2 (240 nM), CDK1 (250 nM), CDK5 (460 nM), GSK-3β, MK2, PLK1, CHK2 | 2 withdrawn phase I clinical trials in advanced solid tumors | (Montagnoli et al., 2008) |
| XL-413 (BMS-863233) | CDC7 (3.4 nM) | PIM1, CK2 | 2 withdrawn phase I and II clinical trials in advanced solid tumors and hematologic malignancies | (Koltun et al., 2012) |
| LY-3143921 | CDC7 (3.3 nM) | 1 active phase I clinical trial in advanced solid cancers | ||
| TAK-931 (Simurosertib) | CDC7 (<0.3 nM) | 3 phase I and II clinical trials in various advanced solid tumors; one on-going | (Iwai et al., 2019) | |
| BS-181 | CDK7 (210 nM) | CDK2 (0.9 μM), CDK5 (3 μM), CDK9 (4.2 μM), CDK1 (8.1 μM), CDK4 (33 μM), CDK6 (47 μM) | not entered clinical studies yet | (Ali et al., 2009) |
| ICEC0942 (CT7001, Samuraciclib) | CDK7 (40 nM) | CDK2 (620 nM), CDK9 (1.2 μM), CDK1 (1.8 μM) | 1 phase I/II on-going clinical trial in advanced solid tumors | (Patel et al., 2018) |
| THZ1 | CDK7 (3.2 nM) | not entered clinical studies yet | (Kwiatkowski et al., 2014) | |
| YKL-5-124 | CDK7 (9.7 nM) | CDK2 (1300 nM) CDK9 (3020 nM) | not entered clinical studies yet | (Olson et al., 2019) |
| SY-5609 | CDK7 (0.6 nM) | CDK2 (2900 nM) CDK9 (970 nM) CDK12 (770 nM), | 1 phase I dose-escalation in select advanced solid tumors | (Sava et al., 2020) |
| SY-1365 | CDK7 (84 nM) | CDK2 (2117 nM) CDK9 (914 nM) CDK12 (204 nM), | 1 phase I dose-escalation/safety advanced solid tumors | (Sava et al., 2020) |
1
Inhibitors of cell- cycle kinases which entered clinical trials of any phase; MAPK - Mitogen-Activated Protein Kinase; PKC – Protein Kinase C; EGFR - Epidermal Growth Factor Receptor; ERK - Extracellular Signal-Regulated Kinase; JAK2 – Janus Kinase 2; FLT3 - Receptor-type tyrosine-protein kinase FLT3; GSK-3β - Glycogen Synthase Kinase 3 beta; TAK1 - Transforming Growth Factor-β Activated Kinase 1; MEK1 - Dual Specificity Mitogen-Activated Protein Kinase 1; MK2 - MAP Kinase-Activated Protein Kinase 2; PLK1 – Polo-Like Kinase 1; CHK2 - Checkpoint Kinase 2; PIM1 - Proto-oncogene Serine/Threonine-Protein Kinase 1; CK2 – Casein Kinase 2; MDS/AML – Myelodysplastic Syndrome/ Acute Myeloid Leukemia, CLL – Chronic Lymphocytic Leukemia