Table 3.
Characterisation of TOPK inhibitors—preclinical studies
| Inhibitor | Model | Sensitivity | Specificty | References |
|---|---|---|---|---|
| HI-TOPK-032 | Kinase activity [% Inhibition] | TOPK (60%) [2 μM HI-TOPK-32] | Other kinase targets: MEK1 (20%), ERK1 (0%), JNK1 (0%), p38 (0%) | 41 |
| Colon cancer cell lines nasopharyngeal carcinoma cell lines | 0.5–5 μM, 10 μM | ↓ Growth, ↓ Anchorage-independent colony formation | 22, 41 | |
| 0.5–8 μM | ↑ DNA fragmentation and cell death, ↑ Intracellular ROS | 43 | ||
| s.c. xenograft | HCT-116 [10 mg/kg t.i.w. (25 days)] CNF-2 [5 mg/kg t.i.w. (14 days)] HT-29 [5 mg/kg t.i.w. (20 days)] |
↓ Tumour growth, No weight loss ↓ Tumour growth, No weight loss Chemosensitisation (oxaliplatin) |
41 | |
| ADA-07 | Kinase assay NHDF, A431 & SCC12 JB6 P + |
Inhibition [5-10 μM ADA-07] 0.625-10 μM 1.25-10 μM |
Co-precipitation, no MEK1 inhibition ↓ Growth, ↓ Anchorage-dependent colony formation ↓ Transformation potential |
42 |
| SUV-induced papilloma formation | [0.1 mg, 1 mg (topical) t.i.w. (28 weeks)] | ↓ Tumorigenesis (early-stage), ↓ Papilloma formation (late-stage) No cytotoxicity |
42 | |
| OTS514 | Kinase activity [% Inhibition] | TOPK (84%) [0.2 μM OTS514] | Other kinase targets: cSrc (61%), FLT3 (44%), FYN (19%), LYN (28%), CDK2/Cyclin A (60%), BTK (12%), DAPK1 (29%), GSK3b (25%), IGF1R (28%), IRAK4 (21%), RET (13%), TAK1 (42%) | 27 |
| SCLC cell lines, Kidney cancer cell lines, Ovarian cancer cell lines | IC50 values: DMS114 (1.3 nM), H69AR (7.3 nM), H446 (8.4 nM), H69 (0.4 nM), H82 (7.2 nM), H146 (39.3 nM), H524 (2.6 nM), H2171 (42.6 nM), DMS273 (4.1 nM), SBC-3 (2.0 nM), SBC-5 (3.7 nM), VMRC-RCW (19.9 nM), Caki-1 (27.8 nM), Caki-2 (20.1 nM), 769-P (20.7 nM), 786-O (44.1 nM), CaOV3 (3 nM), OVTOKO (46 nM). | ↓ Growth, ↑ apoptotic cell death Sensitivity is relative to intrinsic TOPK expression ↓ FOXM1 transcription ↓ TOPK protein expression |
8, 26, 44 | |
| s.c. xenograft | A549, LU-99 [1, 2.5, 5 mg/kg t.i.w. (14 days)] | ↓ Tumour growth, Haematopoietic toxicity (free); slight reduction in body weight (liposomal, high dose) | 27 | |
| Metastatic growth | [25 mg/kg, q.d. (14 days) 50 mg/kg, q.d. (11 days)] |
Abolition of tumour growth in 15% > 20% weight loss in high dose group ↓ Growth, Sensitivity does not vary according to tumour site or histological type |
44 | |
| Ex vivo (patient derived) | Ovarian cancer (10 nM, 100 nM) | |||
| OTS964 | Kinase activity [% Inhibition] | TOPK (80%) [2 μM OTS964] | Other kinase targets: cSrc (88%), FLT3 (72%), FYN (63%), LYN (77%), MELK (61%), CDK2/Cyclin A (44%), BTK (52%), DAPK1 (42%), GSK3b (45%), IGF1R (40%), IRAK4 (43%), PIM1 (59%), RET (41%), TAK1 (44%) | 27 |
| Various cancer cell lines | IC50 values: A549 (31 nM), LU99 (7.6 nM), DU4475 (53 nM), MDA-MB-231 (73 nM), T47D (72 nM), Daudi (25 nM), UM-UC-3 (32 nM), HCT-116 (33 nM), HT29 (290 nM), MKN1 (38 nM), MKN45 (39 nM), HepG2 (19 nM), MIAPaca-2 (30 nM), 22Rv1 (50 nM), CaOV3 (14 nM), RMG-1 (110 nM), Hela (60 nM), MRC5 (185 nM), HFL-1 (175 nM), DU145 (43 nM), PC3 (147 nM), H1299 (88 nM), T24 (153 nM), SQ20B (59 nM), HAP1 (83 nM). | ↓ Growth, ↑ apoptotic cell death Sensitivity is tumour cell line-specific, tumour-specific radiosensitisation |
27, 40 | |
| s.c. xenograft | LU-99 [40 mg/kg i.v. (×6 in 18 days) 50 or 100 mg/kg p.o.] |
↓ Tumour growth with complete regression, transient haematopoietic toxicity |
27 |
Key: ROS reactive oxygen species, s.c. subcutaneous, i.v. intravenous, t.i.w. three times per week, SUV solar ultraviolet radiation, SCLC small cell lung cancer, q.d. daily, p.o. oral dosing