Table 4 Structure and molecular function of CLKs inhibitors
From: Cdc2-like kinases: structure, biological function and therapeutic targets for diseases
Compound name | Chemical formula | Structure | Targets (IC50 or Kd values) | Administration efficiency | Clinical trial status and efficacy | Ref. | |
|---|---|---|---|---|---|---|---|
In vitro | In vivo | ||||||
SM08502 | C24H25N7O |
| 8 nM on CLK1 2 nM on CLK2 22 nM on CLK3 1 nM on CLK4 2–13 nM on DYRKs 1.1 μM on CDK1 | SM08502 inhibited CLKs activity, decreased SRSF phosphorylation, and reduced the generation of splicing variants of Wnt signal pathway genes in gastrointestinal cancer | Oral administration of 6.25 ~ 25 mg/kg SM08502 by QD or QOD inhibited gastrointestinal tumor growth and decreased SRSF phosphorylation in xenograft mouse models | Phase I (NCT03355066) Ongoing Phase I (NCT05084859) Ongoing | |
TG003 | C13H15NO2S |
| 20 nM on mCLK1 200 nM on mCLK2 15 nM on mCLK4 No activity on mCLK3 No activity on SRPK1, SRPK2 and PKC | TG003 reduced cell proliferation, invasion, and migration in gastric and prostate cancer cells TG003 inhibited CLK/STY kinases activities and suppressed phosphorylation of SR proteins in Hela cell line | Intraperitoneal administration of TG003 twice per week decreased prostate cancer CDX growth | NO | |
T-025 | C21H18N8 |
| 0.096 nM on CLK2 4.8 nM on CLK1 6.5 nM on CLK3 0.61 nM on CLK4 0.074 nM on DYRK1 1.5 nM on DYRK1B | T-025 was more effective on cells with high CLK2 expression and Myc-amplification in a dose-dependent manner; facilitating activation of downstream SE events | 50 mg/kg T-025 strongly suppressed the growth of breast tumor allograft model | NO | |
DB18 | C24H18ClN7O3 |
| 11 nM on CLK1 27 nM on CLK2 1280 nM on CLK3 20 nM on CLK4 120 nM on DYRK1A | DB18 showed high inhibitory effects on MCF-7 and PC3 cell lines; weaker inhibitory effects were observed on fibroblast, HuH7, CaCo-2, MDA-MB-231, HCT116 and NCI-H727 cell lines | NO | NO | |
CLK1-IN-1 | C24H16FN5O |
| 2 nM on CLK1 31 nM on CLK2 8 nM on CLK4 138 nM on DYRK1A | CLK1-IN-1 inhibited CLK1 activation, resulting in the distribution of SR proteins and increasing autophagy and autophagic flux | 30 mg/kg CLK1-IN-1 had a hepatoprotective effect by decreasing ALT and AST enzyme levels in an APAP-induced hepatotoxicity mouse model | NO | |
CLK-IN-T3 | C28H30N6O2 |
| 0.67 nM on CLK1 15 nM on CLK2 110 nM on CLK3 260 nM on DYRK1A 230 nM on DYRK1B | T3 induced apoptosis and G2/M cell cycle arrest in A2780 and HCT116 cells; synergistically induced apoptosis with Bcl-xL/Bcl-2 inhibitor | NO | NO | |
KH-CB19 | C15H13Cl2N3O2 |
| 19.7 nM on CLK1 530 nM on CLK3 55.2 nM on DYRK1A | KH-CB19 suppressed the phosphorylation of SRp75, SRp55 and SRp20; reduced flTF and asHTF expression; attenuated TNF-α-induced TF mRNA splice variants in HMEC-1 cells | NO | NO | |
Cpd-1 | C21H20F3N7O |
| 16 nM on CLK1 45 nM on CLK2 61 nM on SRPK1 75 nM on SRPK2 10000 nM on SRPK3 | Cpd-1, cpd-2, and cpd-3 compounds decreased endogenous phosphorylation of SR proteins and enlarged the nuclear speckles in MDA-MB-468 cells; resulting in splicing alterations of S6K and subsequent S6K protein depletion | NO | NO | |
Cpd-2 | C20H20N6O |
| 1.1 nM on CLK1 2.4 nM on CLK2 >100 nM on SRPK1/2/3 | ||||
Cpd-3 | C21H21N5O2 |
| 1.1 nM on CLK1 2.1 nM on CLK2 >100 nM on SRPK1/2/3 | ||||
MU1210 | C22H16N4O |
| 8 nM on CLK1 20 nM on CLK2 12 nM on CLK4 >3000 nM on CLK3 29 nM on HIPK2 159 nM on HIPK3 187 nM on HIPK1 213 nM on DYRK1A 956 nM on DYRK1B 1309 nM on DYRK2 | MU1210 attenuated MCF-7 cell proliferation and exhibited an IC50 of 4.6 μM in cell viability | NO | NO | |
Indazole1 | C19H24N4O |
| 12 nM on CLK1 10 nM on CLK2 2250 nM on CLK3 12 nM on CLK4 73 nM on DYRK1A | Indazole1 increased the frequency of MNBN in a dose-dependent manner through CLKs inhibition in primary human lymphocytes | NO | NO | |
KuWal151 | C16H11ClN2O |
| 88 nM on CLK1, 510 nM on CLK2 28 nM on CLK4 Inactive on CLK3, DYRK1A/B and DYRK2 ( > 10 μM) | KuWal151 exhibited less than 0.5 μM potency in more than 50 cancer cell lines, specifically in MDA-MB-435 cell line (GI50 = 72.4 nM) | NO | NO | |
GPS167 | C17H13N5OS |
| NO | GPS167 impaired cell proliferation and organoids growth of human CRC cells by interrupting the phosphorylation of SRSF10 | NO | NO | |
Silmitasertib (CX-4945) | C19H12ClN3O2 |
| 3.8 nM on CLK2 1 nM on CK2α and CK2α‘ 82.3 nM on CLK1 90 nM on CLK3 1.229 μM on SRPK1 1.111 μM on SRPK2 | CX-4945 inhibited CLK2 kinase activity and modulated SR protein phosphorylation with an IC50 dose between 3 to 90 nM CX-4945 treatment decreased SRSF1, SRSF4, SRSF5, and SRSF6 phosphorylation in 293 T cells | CX-4945 inhibited neoplastic animal models singly or synergistically combined with other inhibitors | Phase I/II (NCT03904862) Recruiting Phase I (NCT03897036) Recruiting Not application (NCT03571438) Recruiting Phase I/II (NCT02128282) Complete | |
CC-671 | C28H28N6O4 |
| 6 nM on CLK2 5 nM on TTK 300 nM on CLK1 99 nM on DYRK3 107 nM on DYRK1A 157 nM on DYRK1B 136 nM on PHKG | Luminal breast cancer cells were more sensitive to CC-671 than TNBC cells | NO | NO | |
Thiophene 48 | C12H8N2S2 |
| 110 nM on CLK1 100 nM on DYRK1A 70 nM on DYRK1B 40 nM on DYRK2 | Thiophene 48 induced cell apoptosis in U2OS osteosarcoma cells at 1 μM by increasing the ratio of caspase 3/7 Thiophene 48 exhibited low toxicity on V79 hamster lung fibroblasts at 5 μM | NO | NO | |
Leucettine L41 | C17H13N3O3 |
| 71 nM on CLK1 64 nM on CLK4 60 nM on DYRK1A 44 nM on DYRK1B 73 nM on DYRK2 720 nM on CLK2 >10 μM on CLK3 | L41 displayed a neuroprotective role in glutamate induced HT22 cell death L41 treatment significantly elevated the percentage of exon inclusion of the CLK1 minigene by modulating pre-mRNA splicing in Hela cells | NO | NO | |
