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. 2021 Jan 15;20:15. doi: 10.1186/s12943-020-01305-3

Table 3.

AKIs in preclinical studies

Compound
names		 Structures Targets
(IC50)		 Cell-based potency
(IC50/EC50/GI50)		 Animal models
(type; concentration; efficiency)		 Ref
CYC3 graphic file with name 12943_2020_1305_Figa_HTML.gif

AURKA

(0.033 μM))

IC50:

MIA PaCa-2 (1.1 μM)

PANC-1 (2 μM)

 NA [79]
AKI603 graphic file with name 12943_2020_1305_Figb_HTML.gif AURKA (12.3 nM) NA Epirubicin resistant MCF-7 cell xenograft; mice were treated intra-gastrically every day with 50 mg/kg AKI603; tumor volume and tumor weight were significantly reduced. [80]
BPR1K0609S1(BP) graphic file with name 12943_2020_1305_Figc_HTML.gif AURKA (43 nM) HCT116 (400 nM) Parental and BP-resistant HCT116 Puma(−), Bax(−), Chk2(−) and p53(−) cells were transplanted into nude mice; these BP-resistant cells did not show faster tumor development compared to their parental cells, respectively. [81, 82]
LDD970 graphic file with name 12943_2020_1305_Figd_HTML.gif AURKA (0.37 μM)

IC50:

HT29 (4.22 μM)

 NA [83]
MK-8745 graphic file with name 12943_2020_1305_Fige_HTML.gif AURKA (0.6 nM) NA HCT116, HCT116 p53(−), HCT116 Puma(−), HCT116 p21(−) and HCT116 Chk2(−) xenografts; MK-8745 (800 nM) was directly s.c. injected daily; HCT116 p53(−) tumorigenesis was weakly inhibited, HCT116 Puma(−), HCT116 p21(−), HCT116 Bax(−) and HCT116 Chk2(−) cells was inhibited with MK-8745. [84, 85]
LY3295668 graphic file with name 12943_2020_1305_Figf_HTML.gif AURKA (< 1 nM) 55 out of 80 cell lines displayed sensitivity (IC50 < 1 μM) to LY3295668 with an average IC50 of 0.048 μM

1. NCI-H446 xenograft model; 50 mg/kg (s.c), (BIDX7, rest 14) X 2, (BIDX14, rest 7) X 2, or (BIDx21) X 2 schedule; produced significant tumor growth inhibition.

2. PDX; 50 mg/kg BIDX28 showed 97.2% of tumor growth inhibition.

 [86]
BPR1K653 graphic file with name 12943_2020_1305_Figg_HTML.gif

AURKA (124 nM)

AURKB (45 nM)

IC50:

A549 (9 nM)

HT29 (12 nM)

OECM-1 (135 nM)

HONE-1 (11 nM)

KB (12 nM)

NTUB1 (8 nM)

MV4–11(5 nM)

IM9 (4 nM)

Cervical cancer KB xenograft;

15 mg/kg through intravenous injection for two weeks;

73% decrease in tumor volume.

 [87]
TY-011 graphic file with name 12943_2020_1305_Figh_HTML.gif

AURKA (102.1 nM)

AURKB (93.9 nM)

IC50:

SNU-16 (0.09 μM)

MKN-45 (0.13 μM)

MGC-803 (0.19 μM)

SGC-7901(0.57 μM)

AGS (0.96 μM)

 Gastric cancer cell MGC-803 xenograft; TY-011 was orally administered at 3, 6 and 9 mg/kg once a day for 13 days; 64.9, 87.7, 89% inhibition rate for 3, 6 and 9 mg/kg respectively. [88]
BPR1K871 graphic file with name 12943_2020_1305_Figi_HTML.gif

AURKA (22 nM)

AURKB (13 nM)

FLT3 (19 nM)

EC50 values ranged from 34 nM to 7 μM in various cancer cells.

COLO205 (34 nM)

Mia-PaCa2 (94 nM)

 Colorectal COLO205 or pancreatic Mia-PaCa2 xenograft; 15 mg/kg intravenous administration of BPR1K871 once a day for two continuous weeks (on days 1–5 and 8–12); TGI was about 90%. [89]
SCH-1473759 graphic file with name 12943_2020_1305_Figj_HTML.gif

AURKA (≤4 nM)

AURKB (≤ 13 nM)

 In 51/53 tumor cells IC50 < 100 nM. The mean IC50 was 21 nM. A2780, LNCap, N87, Molt4, K562, and CCRF-CEM with IC50 < 5 nM. A2780 human tumor xenograft; 5 mg/kg (i.p) bid dosed daily on days 0–16 (TGI = 50%) and 10 mg/kg (i.p) bid dosed intermittently on days 0–4 and 10–14 (TGI = 69%). [90]
Derrone graphic file with name 12943_2020_1305_Figk_HTML.gif

AURKA (22.3 μM)

AURKB (6 μM)

H1299 (23.8 μM)

MCF7 (24.4 μM)

Hela (31.2 μM)

KPL4 (45.8 μM)

 NA [91]
JNJ-7706621 graphic file with name 12943_2020_1305_Figl_HTML.gif

AURKA (11 nM)

AURKB (15 nM)

CDK1 (9 nM)

CDK2 (4 nM)

 IC50 values ranged from 112 to 514 nM in various cancer cell lines while IC50 values ranged from 3.67 to 5.42 μM in normal cells. A375 xenograft model; JNJ-7706621 was treated i.p using 125 mg/kg 7 on/7 off schedule and the 100 mg/kg QD schedule; TGI values were 93% for both two schedules. [92]
SAR156497 graphic file with name 12943_2020_1305_Figm_HTML.gif

AURKA (0.6 nM)

AURKB (1 nM)

AURKC (3 nM)

 SAR156497 was active on various tumor cell lines (IC50: 5–500 nM). HCT116 xenografts; compound was s.c injected in continuous infusion using ALZET micropump at an 8 μL/h flow rate for 48 h and at doses of 25 mg/kg; TGI% = 81%. Note: therapeutic window was narrow. [93]
R1498 graphic file with name 12943_2020_1305_Fign_HTML.gif

VEGFR2 (25 nM)

AURKA (67 nM)

AURKB (167 nM)

Mean IC50s were

7.81, 7.55 and 30.07 μM in epatocellular carcinoma, gastric cancer, and nasopharyngeal carcinoma cell lines, respectively.

1. BEL-7402, MGC-803 and SGC-7901 xenografts; 25 mg/kg, twice daily, orally; R1498 showed better TGI% over sorafenib.

2. CNE-2 xenograft; 25 mg/kg, twice-daily, oral gavage; TGI% was 90%.

3. Three PDX model; TGI% reached 73.6–91.6% (25 mg/kg, twice-daily, oral gavage).

 [94]
VE-465 graphic file with name 12943_2020_1305_Figo_HTML.gif

AURKA (1 nM)

AURKB (26 nM)

AURKC (8.7 nM)

Huh-7 (2.01 μM)

HepG2 (4.15 μM)

 HCC human Huh-7 xenograft; twice a day i.p with VE-465 at 15, 25, and 35 mg/kg for 14 days; the mean tumor volumes were reduced by 59, 59, and 77%, respectively. [95]
CCT129202 graphic file with name 12943_2020_1305_Figp_HTML.gif

AURKA (0.042 μM)

AURKB (0.198 μM)

AURKC (0.227 μM)

GI50:

Colo205 (0.46 μM)

SW620 (0.7 μM)

HCT116 (0.35 μM)

HT29 (0.5 μM)

KW12 (1.2 μM)

Hela (0.2 μM)

A2780 (0.3 μM)

OVCAR8 (1 μM)

MV4–11 (0.08 μM)

HCT116 colon carcinoma xenografts; mice were treated i.p. with a single dose of 100 mg/kg /day for 9 days;

Significant tumor growth inhibition was observed compared with the

vehicle-treated mice (% treated versus control, 57.7; P = 0.0355)

 [96]
CCT137690 graphic file with name 12943_2020_1305_Figq_HTML.gif

AURKA (0.015 μM)

AURKB (0.025 μM)

AURKC (0.019 μM)

FLT3 (0.0025 μM)

 CCT137690 effectively inhibited the growth of human tumor cell lines of different origins with GI50 values ranging from 0.005 to 0.47 Μm.

1. SW620 xenografts; orally at a dose of 75 mg/kg twice a day for 21 days; The treated/control (T/C) ratio was calculated as 42.4% based on final tumor weight.

2. MYCN-driven transgenic mouse model; 100 mg/kg twice daily for 10 days; TGI was observed as early as day 3 and continuous treatment showed significant tumor growth inhibition at day 7 and day 10.

 [97, 98]
PHA-680632 graphic file with name 12943_2020_1305_Figr_HTML.gif

AURKA (27 nM)

AURKB (135 nM)

AURKC (120 nM)

 PHA-680632 has potent antiproliferative activity in a wide range of cell types with an IC50 in the range of 0.06 to 7.15 μM.

1. HL60 xenograft; mice were injected i.v. at three dose levels (15, 30, and 45 mg/kg for 5 days); the 45 mg/kg dose resulted in 85% of TGI without signs of toxicity.

2. A2780 xenograft; 60 mg/kg i.v. for 5 days; TGI% = 78%.

3. HCT116 colon carcinoma xenograft; 15 and 30 mg/kg i.p for 12 days; TGI was 75%.

 [99]
AKI-001 graphic file with name 12943_2020_1305_Figs_HTML.gif

AURKA (0.004 μM)

AURKB (0.005 μM)

HCT116 (0.07 μM)

HT29 (0.07 μM)

MCF7 (0.1 μM)

HCT-116 xenograft model;

Mice were dosed orally QD for 21 days (0, 1, 2.5, 5, or 10 mg/kg); 2.5 (82% TGI) and 5 mg/kg (92% TGI). Note: dosing at 10 mg/kg QD led to unacceptable weight loss, marked bone marrow depletion, and gastrointestinal hypocellularity.

 [100]
Reversine graphic file with name 12943_2020_1305_Figt_HTML.gif

AURKA (400 nM)

AURKB (500 nM)

AURKC (400 nM)

 IC50 values ranged from 100 to 1000 nM of a wide variety of tumor cell lines. U14 cell xenograft; mice were treated with reversine (10 mg/kg) alone or with aspirin (1 μg/kg), i.p per 3 days; tumor growth was reduced and the mice survived longer in the combination group. [101]

Tumor growth inhibition (TGI); Intraperitoneal injection (i.p); Subcutaneous (s.c); Intravenous (i.v); Growth inhibition by 50% (GI50); Twice a day (BID); Once a day (QD); NA: not available