Table 3 Characterisation of TOPK inhibitors—preclinical studies

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