PLK targets as anti-cancer agents

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Discovery of inhibitors of Aurora/PLK targets as anti-cancer agents Baowen Qi, Ling Zhong, Jun He, Hongjia Zhang, Fengqiong Li, Ting Wang, Jing Zou, Yao-Xin Lin, Chengchen Zhang, Xiaoqiang Guo, Rui Li, and Jianyou Shi J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.9b00353 • Publication Date (Web): 05 Aug 2019 Downloaded from pubs.acs.org on August 6, 2019

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Journal of Medicinal Chemistry

Engineering Li, Rui; State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Shi, Jianyou; Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, Individualized Medication Key Laboratory of Sichuan Province, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, School of Medicine, Center for Information in Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.

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Journal of Medicinal Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Discovery of inhibitors of Aurora/PLK targets as anti-cancer agents

Baowen Qi1,5, Ling Zhong2, 3, Jun He4, Hongjia Zhang2, Fengqiong Li2, Ting Wang2, Jing Zou2, Yao-Xin Lin5, Chengchen Zhang2, Xiaoqiang Guo1, Rui Li4*, Jianyou Shi2*

1College

of Pharmacy and Biological Engineering, Chengdu University, Chengdu 610106, China.

2Sichuan

Academy

of Medical Science & Sichuan Provincial People's Hospital, Individualized Medication Key Laboratory of Sichuan Province, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, School of Medicine, Center for Information in Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.

3Chengdu

Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China. 1


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4Cancer

Center, West China Hospital, Sichuan University, and Collaborative

Innovation Center for Biotherapy, 610041, China.

5Center

for Nanomedicine and Department of Anesthesiology, Brigham and

Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States.

ABSTRACT

Aurora and Polo-like kinases control the G2/M phase in cell mitosis, which are both considered as crucial targets for cancer cell proliferations. Here, naphthalene-based Aurora/PLK co-inhibitor as leading compound were designed through in silico approach and a total of 36 derivatives were synthesized. One candidate (AAPK-25) was selected under in vitro cell based high throughput screening with an IC50 value=0.4 μM to human colon cancer cell HCT-116. A 2



kinome scan assay showed that AAPK-25 was remarkably selective to both Aurora and PLK families. The relevant genome pathways were also depicted by microarray based gene expression analysis. Furthermore, validated from a set of in vitro and in vivo studies, AAPK-25 significantly inhibited the development of the colon cancer growth and prolonged the median survival time at the end of the administration (p140) binding for the most functional kinase Aurora A(PDB code: 2DWB)32 and PLK1 (PDB code: 2RKU)33 was obtained respectively. Finally, the binding patterns of these compounds were then predicted using the CDOCKER docking module according 6



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to previous reported.34 After visual inspection of the binding positions, it was found that a 6-amino-2-naphthoic acid structure had the highest crossing binding energy with both Aurora/PLK kinases. The preliminary in vitro cytotoxicity results showed that one selected compound has the best inhibitory effect on Aurora and PLK highly expressed cell lines, especially on HCT-116 human colon cancer cells (IC50=0.4 μM), as an optimal model cell line to explore the mechanisms of the

selected

compound.

Results and discussion In silico design and synthesis of Aurora/PLK inhibitors Using the CDOCKER docking module, we found that 6-amino-2-naphthoic acid structure showed the highest binding energy with both Aurora/PLK kinases. Briefly, for the binding mode of 6-amino-2-naphthoic acid to Aurora-A, the nitrogen atom of the peptide bond adjacent to terminal benzene in AAPK-25 formed AAPK-25 a hydrogen bond with the Leu139 amino acid residue in Aurora7


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A, while the nitrogen atom of the other peptide bond in AAPK-25 also interacted with the Asn261 amino acid residue via a hydrogen bond. In addition, the 3, 4dichlorobenzene group formed a pi-cation interaction with the Lys143 amino acid residue (Figure 1A). It was also discovered that the terminal benzene ring could interact with the Phe172 amino acid residue in Aurora-B to form a π - π bond (Figure 1B). Similarly, thiazole ring of AAPK-25 also has a π - π interaction with the Glu140 amino acid residue in PLK-1 (Figure 1C). For PLK-2, the carbonyl group adjacent to the naphthalene rings formed a hydrogen bond with the Cys133 amino acid residue, in contrast to the nitrogen atom on the oxazole ring demonstrating a hydrogen bond interaction with the Lys57 amino acid residue. In addition, the 3, 4-dichlorobenzene group had π-π interactions with Phe183 amino acid residue, accompanied with the halogen bond formation between 4-chlorine and the Asp194 amino acid residue (Figure 1D). The ranking score was calculated on their CDOCKER energy (kcal·mol-1) according to the docking protocol for the evaluation the affinity between the ligands and the kinases. Generally, 6-amino-2-naphthoic acid had the optimal energy to the potential 8 ACS Paragon Plus Environment


binding site of -56.96 kcal·mol-1 with Aurora-A and -28.63 kcal·mol-1 with AuroraB, while demonstrated -45.27 kcal·mol-1 with PLK-1 and -32.55 kcal·mol-1 with PLK-2, respectively (the docking result of Aurora inhibitor MLN-8237 and PLK inhibitor BI2536 was shown for the comparison in the supporting information data). Therefore, 6-amino-2-naphthoic acid analogs were presumably being able to exert the strongest drug-like properties among the compound library, functioning as potential inhibitors to both Aurora and PLK according to the above virtual screening result. Considering the structural diversity of the hits, 6-amino-2-naphthoic acid skeletal structures based 36 compounds were synthesized and illustrated in the Figure 1C. Briefly, aryl-substituted acid was acylated by the thionyl chloride to produce corresponding acyl chloride (a) at 80°C, then the nucleophilic reaction of the amino group of 6-amino-2-naphthoic acid with the different acryl chloride (a) was carried out using N, N-Diisopropylethylamine as the catalyst in tetrahydrofuran at 0°C to produce the intermediate (b). Finally, this intermediate b and distinct amines were in a condensation reaction to produce the naphthalene compounds 9 ACS Paragon Plus Environment

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(c), with carbodiimide as the condensing agent. All the chemical structures of 36 compounds were shown in the Fig.1. The NMR and LC-MS characterizations of all 36 compounds were shown in the SI compound synthesis part.

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(A) O

R1 1:

R (A)H N i Cl a (A(A) R )N N

OH O

R1

1

OH

F

R1 =

R1 =

R1 =

4:

R1 =

R2R =

O N H

1

F

N

R2 =

F

6:

R1 =

F

AAPK-2: R1=

F

1:

F

R1 =

3:

C7:

4:

5:

F C9:

RF = R2 = O

R1 =

F

R1 =

H O N =

R2 R1 =

7:

C11: R1= R2 =

R1 =

b

3

R 2= O

O

AAPK-19: R1=

2

R2=

O

AAPK-20: R1=

O1= 24: R

FR32=C N

Cl

R 2=

N

C12: R1=

R2 = R2 = R2 =

NO

H

14: R1=

R2 = R2 =

O H

R2 =

N

N

C26: R1= R2 =

R2 =

O

16: RS 1=

H N

S N

N

17: R1=

R 2=

O R 2=

N

R2=22: R1=

F3O C

F3C

F3C Cl Cl

(E)

N

N

N

N

N N

O N O

N

Cl O Cl

H Cl S N R2= Cl C45: R1= N Cl

R2 =

O N

Cl

AAPK-45: R1=

R2 = 29: R1= R2 =

O N

N

N

Cl

S

R2 =

N

O

R2 =

O R 2=

R 2=

R 2=

N

R228: = R 1=

AAPK-44: R1=

R 2=

N

c

R2 N

N

C l

S N N

RO2=

S

R2 =

N

30: R1= R2 =

R2 =

R231: = RN=

R2 =

33: R1=

R2 =

O N

Cl

R2 =

S

R2 =

R 2=

35: R1=

36: R1=

O

N

N

H N H N

S N

H N N H N

N

34: R1= R2 =

N

R 2=

R2 = N 32: R1=

C44: R1=

O

1

R2 =

AAPK-43: R1=

Cl

N

N

1

1

C43: R1=

O

N O

R 2=

Cl

Cl Cl

N

S

N N Cl

Cl

N R2 = Cl

R =N O iii AAPK-41: R2 = N R 2= R 1 N AAPK-42: R = H Cl N

CF3

Cl ClH

R2 =

Cl

R2 =

(D)

R2 =

NR = 2

AAPK-40: R1=

O

C41: R1=N R 2=

R2 =

N N

AAPK-39: R1R = 2=

O

Cl H Cl

O 27: R1=

O

H Cl N

R 2=

NCl

1

Cl

O

26: R1=

R2 = AAPK-37: R1=

O AAPK-38: R =

N

C42: R1=

F3CCF3

2

C38: R1H = R2 = Cl

R 1=

25: R1= R2=

S N

NR =

Cl

C40: R2=R1=

O

H N

C37: O R2 =

21: R N1= R2=

R2=

N

O R1 =

R = C39:2 R = 1

24: R1=

F3C

AAPK-35: R1=

AAPK-36: R1=

2

N Cl 20: R1= S F3C R2= N

N

F3C

C30: RR1== 2

F3C

R2=

F3CH

O

R2=

R 2=

ClR =

O

R2 = R2=19: R1 = N

CF3 R2=23:

F3N C

N

18: R1=

O

H N

R 2= C28: R1=

O N

F3C

H N

C27: R1=H

R21== C29: R

NN N

AAPK-27:R1=

2

Cl

O

O 15: R1=

N C23: RN1=

Cl

C25: RR=1=

12: R1=

R2= 13: R1= O R2 =

1

R2 =

R = C24: R2 = 1

N

N

Cl H R1=NAAPK-26:R = Cl

R 2=

O

N

O

H N

N

R 2=

O

11: R1=

ON

C15: RR 1== 2

C22:

O

R1 =

(C)

N

O

R 2=

R 2=

1

N

S

N

R2 =

F3C

O

O

N

R2 =

R2 =

CF3 Cl

=

R2

R2 =

Cl

F3C C32: R1 = N R2 = 33: R1= AAPK-29:R1= O F3C R 2=

N

R2 =

Cl

31: R1 =

N H

OH

R2 =

Cl

F3C32: R1

R 2= AAPK-28: R1=

N

(B)c

Cl

30: R1 =

C31: R1=

2 23: R1= O F C 3 R =

CF3

CF3

CF3R2=

(C)F C （） R =

N

=

29: R1 =

R 2=

F3C

22: R1=

C18: R1= O

R2 =

AAPK-18: R1=

CF3 N

O 9:

N

R2 =

R 2=

AAPK-17: R1=

R2= 10:

NN S

O

R2 =

R1 =

CF3

1

O

O 8:

15:O R1=

(C)

N

R2 = C14: R1=

R1 =

R 2= R2 =

O C17:NR1= Cl

O CF R23=AAPK-12:16: R1 = R 1=

N

OH

F

F

NR = R2 =

R2 = O

R1 =

21: R1=

C16: R1=

1

O

O

R1 =

C13: R1= 6:

N

2

F

C10: R R12= =

F

N

R2 =

F

F

R1 =

S

2

S

O 14:N R =

AAPK-11: R1=

RR 2=2=

AAPK-8: R1= 1

C8:

R1 =

28:

N

N H

N H R1

N C33: R1= O S AAPK-21: R1= R = RCl= AAPK-30: N R34: = R1 R 2 = R 1= S 25: 2R1= 2 NN O2 = F C N O N 3 O Cl N C4: RR=F1= C19: R1= AAPK-22:R1= Cl R2 = N AAPK-31: R1=C34: R = R2= AAPK-13: R1= R2 = O AAPK-4: O 1 1 O O R2 = OO F3C Cl R2= NN RCl2= 35: R1= 26: R1= 8: R1= N N R2 = R 1= 17: R2 = O N Cl R = O 2 Cl N F O F N N R2 = N O R1= Cl AAPK-23: O RO AAPK-32: R1= AAPK-14: R1= 2= R2 = AAPK-5: R1= R2=O OHN C20: R1OH C5: Ri 1= = N O FC35: R1 = 3C ii Cl R2= NO N O O R2 = O S O 36: R = F O R 1= O O S R = 27: R1= N Cl 18: N 1 9: AAPK-33: O R = 2 AAPK-6: R2 = 1 R1=R1= F R R2R AAPK-24: R1= O AAPK-15: RR12= R2 = OH N 1 = 2= Cl R2 = N OH2N R1= N O N O SH Cl C21: R1= C6: R1= C36: R1O= O F CF R = Cl R2=AAPK-16: R = a b R1 = 3 AAPK-25: 2 AAPK-34: S AAPK-7: R1= R2 = R =

AAPK-9: R1=

2:

N

R 2=

F3C

R2=O

AAPK-10: R1=

R2 =

S

R2 =

F

R1

N

R2 =

C3: RF1= F 7:AAPK-3: R1=R1=

O

N

R2 =

20: R1=

O

13: R = 1

N

R2 =

NH R2R =

12: R1=

R2 =

F

F

C2: FR1=

R2 =

F3C

R1

O

ii

19: R1=

R2 =

O

O

O

iii

R1

H 2N

R1=a

c

R2 =

R1 =

AAPK-1: R1=

Cl

O

CF3

O

C1: FR1=

5:

O

+

11: R1=

N

F

3:

1

OH

O O R1 N H OH b

ii

O O

S

R2 =

iii

O

10:

R2 =

F

2:

OH

2

(B)

O

O

O

i

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R 2=

R 2=

R 2=

N S

N N

O

H N

Figure 1. In silico design of Aurora and PLK dual inhibitor. Binding mode of 6amino-2-naphthoic acid structure was shown with Aurora-A (A. PDB code: 2DWB), Aurora-B (B. PDB code: 5K3Y), PLK-1 (C. PDB code: 2RKU), and PLK2 (D. PDB code: 4I5M). (E) Synthesis of the naphthalene-based compounds as 11 ACS Paragon Plus Environment

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Aurora and PLK dual inhibitors. Reagents and conditions: (i)SOCl2, DMF, 80°C, 2h; (ii)DIEA, THF, 0°C, 3h; (iii)EDCI, DMAP, THF, rt, 4h. The details of synthesis and characterization of the compounds were shown in the supporting information data. In vitro anti-tumor activities of AAPKs All the 36 compounds were assessed in an MTT assay for the evaluation of their inhibition effect on the different cancer cell line growth. Herein, HCT-116, MCF-7, A549 and Calu-6 were selected for the anti-proliferation assay. The criteria to choose these cell models are because they are all dual Aurora and PLK high expressed cell lines according to extensively literature review.23,

35-41

Among those 36 compounds, 6, 11, and 25 suppressed all of cell lines (SI Table 2). In this assay, the IC50 value of AAPK-25 against HCT-116 was 0.4 μM, which demonstrated the highest inhibitory effect among others (Figure 2). This result is in accordance with the previous investigation by using AZD1775, a WEE1 tyrosine kinase/ PLK co-inhibitor, that demonstrated an IC50 value ~ 0.35 μM.42 In addition, IC50 value of selective Aurora inhibitor MLN8237 on HCT-116 cell is 32 μM43 and the IC50 value of selective PLK inhibitor BI2536 on HCT-116 cell is



0.83 μM.23 Thus, our dual inhibitor AAPK-25 is more potent as an antiproliferative agent and therefore selected for further in-depth biological analysis. In addition, AAPK-25 contains 6 hydrogen-bonded donors and 2 hydrogenbonded receptors. The relative molecular mass of AAPK-25 is ~441.01 with a lipid-water partition coefficient of 4.8, which matches the Lipinski rule of five in a rational manner. The solubility of AAPK-25 is ~9.6 µg/mL in water and ~286

HCT116 (IC 50=0.4 µM)

100 80 60 40 20 0 120

(C)

0

1

Log [AAPK-25 μuM]

A549 (IC 50=11.6 µM)

60 40 20 0 0

1

Log [AAPK-25 μ uM]

120

(B) Calu6 (IC 50=5.3 µM)

100 80 60 40 20 0

2

100 80

Cell Viability (% of control)

(A)

120



µg/mL in DMSO at 25±0.2°C.


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120

(D)

0

1

Log [AAPK-25 μ uM]

100

2

MCF7 (IC 50=2.3 µM)

80 60 40 20 0 0

2

1

Log [AAPK-25 μ uM]


2

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Figure 2. IC50 value of AAPK-25 on different cell lines. Cell lines were treated with a range of concentrations as indicated to assess the cytotoxic activity of AAPK-25. Cell lines were exposed to drugs for 48 h. 20 μl of MTT reagent was administered to each well, and absorbance measurements were taken at 490 nm. Cell lines studied were: (A)HCT-116, (B) Calu6, (C)A549 and (D) MCF-7. All values are normalized from cell viability values treated by AAPKs in relative to vehicle control expressed by 100%, representing for n = 3 independent experiments. Cytotoxicity IC50 values for other AAPKs are shown in the SI in vitro cellular screening part. Kinome and genome profile of AAPK-25 by microarray analysis Aurora and PLK families involved in cell cycle division and mitotic progression are promising targets for cancer therapy.44-46 Here, we measured cell cycle kinome expressions to identify the specific kinases that might be therapeutic targets of AAPK-25.47 A profile of 321 kinases using the KINOMEscan competition assay48 at a concentration of 10 μM is performed to comprehensively investigate the selectivity of AAPK-25 followed by determination of binding affinities of Aurora and PLK families. Aurora and B, PLK1 and 2 were the most frequently targeted kinases (Figure 3A). As expected, AAPK-25 also possibly interacted with a subset of kinases such as ERK and PI3K families, which are regulator of Aurora and PLK according to previous study.49-50 For 14 ACS Paragon Plus Environment


instance, it was demonstrated that modulation of ERK activity can alter Aurora expression, indicating that the ERK inhibition was accompanied with the inhibition of Aurora. As such, Aurora kinase A inhibitor (MLN8237) was validated via the inhibition of ERK/PI3K signaling pathway,51 while PLK inhibitor BI2536 can also inhibit ERK simultaneously in tamoxifen-resistant breast cancer cells model.52 Correspondingly, wortmannin, a classical PI3K inhibitor was reported to inhibit PLK concurrently.53 Taken together, our results indicated that AAPK-25 possessed highly selective profiles with Aurora and PLK families in terms of KINOMEscan selectivity score, but also in associated with the other Aurora and PLK relevant kinases. In order to assess the influence of AAPK-25 to all possible relevant pathways in genome level, we used gene microarray analysis to assess its related genes and pathways under the concentration of AAPK-25 in 10 µM for 48 hours.54 The microarray data implied that 121 genes were significantly upregulated and 173 genes markedly down-regulated. The hierarchical clustering heat map analysis showed differentially expressed genes in the AAPK-25 and 15 ACS Paragon Plus Environment

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DMSO control groups (Fig. 3B). The expression of red represented that the gene expression is relatively up-regulated, while the expression of the green indicates that the expression of the gene is relatively down-regulated. The AAPK-25 regulated genes included heat shock protein, cell division cycles, MAP kinase and centrosomal protein, which are reported as shared gene networks.55-58 To further determine which signaling pathways were involved in the possible mechanism of AAPK-25, we selectively to calculate the significance level of the gene enrichment of each pathway according to Gene Ontology (GO) classifications of several major signaling pathways, including cell cycle, p53, and MAPKs, which play important roles in regulating tumor proliferation and metastasis.59 The most enriched GO pathways associated with the anti-cancer effect of AAPK-25 are shown in Fig. 3C. It was confirmed that AAPK-25 is in notably inhibition of the mitotic spindle checkpoint, which is mainly mediated by cell cycle signaling and mitotic pathways. The data was also correlated well with the KINOMEscan result, such as involved ERK inhibitions. Furthermore, the fact that 16 ACS Paragon Plus Environment


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AAPK-25 suppressed cellular metabolic stress response intrinsically due to the inhibition of Aurora,60 accounts that AAPK-25 can be developed as alternative cell death triggers for cancer therapy. Combined by the kinome and genome

(A)

analysis, we can conclude that AAPK-25 has a specifically targeting to Aurora and PLK families via the influence of several their relevant pathways.

O

AAPK-25

N H

O Cl

(A)

N

(B)

S

N H

(A)

Cl

MAPK

Aurora-A PLK-1

AAPK-25

(B)

CDK

(A) ERK

(B)

AAPK-25(B)

DMSO DMSO

(B)

PI3K

(A)

Kinase Kd Value (

PLK targets as anti-cancer agents

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