the discovery of azd4547

The discovery of AZD4547:

David AndrewsAstraZeneca

27th June 2014AnorcQ Industrial Summer School

An orally bioavailable, potent and selective N-(5-Pyrazolyl) benzamide FGFR1-3 inhibitor

2

FGF / FGFR signaling

FGFR1

P

P

P

P

P

P

P

P FGFR4

18 secreted ligands4 non-secreted ligands

Proliferation / migration /anti-apoptosis / angiogenesis

FGFR3FGFR2

Four FGF receptors, FGFR1-4, but multiple splice variants in extracellular ligand binding domain create many more receptor isoforms with different ligand binding specificities

Targeting FGFR kinase inhibition the four receptors have different, but highly homogous, kinase domains

3

FGF / FGFR signaling

FGFR1

PPP

P

PPP

P FGFR4

18 secreted ligands4 non-secreted ligands

FGFR3FGFR2

whole kinase domain sequence homology (276-277 residues)

FGFR1 FGFR2 FGFR3 FGFR4

FGFR1 100%

FGFR2 88% 100%

FGFR3 86% 89% 100%

FGFR4 77% 78% 81% 100%

"key" ATP site homology (81 residues)

FGFR1 FGFR2 FGFR3 FGFR4

FGFR1 100%

FGFR2 94% 100%

FGFR3 91% 90% 100%

FGFR4 89% 89% 93% 100%

Early pharmacological tools – Parke Davis FGFR inhibitors

4

N

N N

O

O

NH

ONH

NH

N

N

N N

O

O

NH

ONH

NH2

PD173074PD166866

J. Pharmacol. Exp. Ther. 1998, 286(1), 569J. Med. Chem. 1998, 41(11), 1752J. Med. Chem. 1997, 40(15), 2296 Bioorg. Med. Chem. Lett. 1997, 7(18), 2415

Binding mode of PD173074

5

N

N N

O

O

NH

ONH

NH

N

PD173074

Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domainEMBO J 1998, 17(20): 5896

VEGFR & FGFR kinase inhibitor drugs in clinical development

6

NH

NH

N N NNH2F

OTKI258Dovitinib

TKI258 / Docitinib: Blood 2005, 105, 2941BIBF 1120 / Intedanib: Cancer Res. 2008, 68, 4774BMS-582664: Brivanib alaninate: Clin. Cancer Res. 2008, 14, 6146

N

N

O

NH

F

NO

O

O

NH2

BMS-582664Brivanib alaninate

NH

NH

N N

O

N

OO

O

BIBF-1120Intedanib

Phase IIIRenal cell cancer Phase III

Non-small cell lung cancerOvarian cancer.

Phase IIIHepatocellular cancer. Colorectal cancer

7

Aberrant regulation of FGF/FGFR signaling occurs in many human tumors

FGFR1

P

P

P

P

P

P

P

P FGFR4

18 ligands

Proliferation / migration /anti-apoptosis / angiogenesis

FGFR3FGFR2

Colorectal and Hepatocellular cancerUp-regulated FGF19

Non-invasive bladder cancer Mutations ~70% tumors

Multiple myeloma Translocation ~20% tumors

Gastric cancerAmplification ~5% tumors

Endometrial cancerMutations ~15%

Breast cancerAmplification ~10% ER +ve

Squamous NSCLCAmplification ~15%

Prostate (FGFR1 and 4)Up-regulated FGFR4 and FGF ligands

Recently reported FGFR inhibitors

8

N

N

N

O

N

HCl

Cl

O

O

NH

N

N

NVP-BGJ398

BGJ398 J. Med. Chem. 2011, 54, 7066 LY2874455 Mol Cancer Ther 2011, 10(11): 2200

N

Cl

Cl

O

NH

N

NN

OH

LY2874455

IC50 nMFGFR1 2.8FGFR2 2.6FGFR3 3.4FGFR4 6KDR 7

IC50 nMFGFR1 0.9FGFR2 1.4FGFR3 1.0FGFR4 60KDR 180

Identification of AZ FGFR hit compounds

9

Screening of compounds prepared in an IGF1R TKI project in a kinase panel highlighted some pyrazolylaminopyrimidines that were more potent against FGFR than other kinases in the panel.

A key project aim was to identify compounds that are selective inhibitors of FGFR suitable for in vivo testing in order to identify FGFR driven effects. In particular this meant selectivity with respect to VEGFR.

Crystal structure and SAR analysis was used to guide chemistry to achieve desired selectivity goal.

N

N

N

NH

N

NH

Br

H

NO

RA Norman, A-K Schott, DM Andrews, J Breed, KM Foote, AP Garner, et al Protein-ligand crystal structures can guide the design of selective inhibitors of the FGFR Tyrosine Kinase. 2012. J. Med. Chem. 55 (11), pp 5003–5012

Pyrazolylaminopyrimidines SAR (1)

10

N

N

N

NH

N

NH

R1

Br

H

Cpd R1FGFR1 enzyme

KDR enzyme

IGF1R enzyme

1540 590 6000

2670 920 4200

369 680 7800

432 3600 9100

O N

O N

N

IC50 (nM)


11

N

N

NH

NH

NR2

NH

Br

NO

Cpd R2FGFR1 enzyme

KDR enzyme

IGF1R enzyme

3 Me69 680 7800

557 1100 18000

69.8 150 370

72.4 23 6800

O

IC50 (nM)

Early hit SAR: Compound 7

12

N

N

NH

NH

N

NH

Br

NO

ClogP 4.3

Aqueous Solubility pH7.4 (M) 1.8

PPB (% Free) rat / man 0.6 / 0.1

Hep Metabol Clint (µl/min/1E6) rat / man 118 / 259

CYP IC50 1A2 / 3A4 / 2C9 / 2C19 / 2D6 (M) <0.1 / 0.23 / 0.75 / 0.99 / >10


13

Cpd X R2FGFR1 enzyme IC50 (nM)

pFGFR1 cell assay IC50

(nM)LogD

8 Br cPr 50 - 3.4

9 Cl cPr 40 - 3.3

10 H cPr 40 - 2.5 *

11 H 1.8 60 3.1

R2

NNH

NH

N N

NH

N

O

X

MeO

OMe

* estimated

hERG IC50 (M) 8.4Aqueous Solubility pH7.4 (M) 0.58Hep Metabol Clint (µl/min/1E6) rat 44CYP IC50 1A2 / 3A4 / 2C9 / 2C19 / 2D6 (M) >10 / <0.1 / 2.6 / >10 / >10

Compound 11 properties

Pyrazolylaminopyrimidines summary and next steps…..

14

• Pyrazolylaminopyrimidines inhibitors provided potent and selective FGFR inhibitors and understanding of SAR.

• However the physical and ADME properties of the more potent pyrazolylaminopyrimidines were far from acceptable.

• To improve on these aminopyrazole based inhibitors of FGFR1, we sought to identify alternative compounds, containing this key hinge binding motif, that could provide a less intrinsically lipophilic start point for developing FGFR inhibitors.

NNHNH

O

N NCompound 12

• As part of this effort, compound 12 was synthesized and found to be a sub-micromolar inhibitor of FGFR1

N-(5-Pyrazolyl)benzamide SAR

15

Cpd R1FGFR1

enzyme IC50 (nM)


(nM)LogD

Aq. Sol. (M)

12 cPr 66 610 2.4 * -

13 0.7 19 3.1 27

14 0.9 6.0 3.2 1.4

MeO

OMe

O

MeO

OMe

* estimated

R1

NNH

NH

O

N

N

Characterization of lead pyrazolylbenzamideCompound 13

17

MeO OMe

N

NH

NH

O

N

N

FGFR1 enzyme IC50 (nM)

KDR enzyme IC50 (nM)


(M)

pKDR cell assay IC50

(M)

0.7 210 0.019 0.24

LogDpH7.4

Aq. Sol. pH7.4 (M)

PPB rat /hu (%free)

pKahERG IC50

(M)

3.1 27 3.4 / 5.7 7.6 >30

CYP inhibition IC50 (M)

1A2 3A4 2C9 2C19 2D6

>10 7.5 >10 >10 >10

Hydrolytic stability T1/2 (days)

pH 1 pH 4 pH 6 pH 8 pH 10

43 >1000 >1000 375 223


18

MeO

OMe

NNH

NHO

N

N


19

0

5

10

15

20

25

30

<10 10-20 20-30 30-40 40-50 50-60 60-70 70-80 80-90 >90

Coun

t of k

inas

es in

inhi

biti

on b

and

% inhibition

Kinase selectivity screening(Dundee consortium panel)

compd 6: 1µM, ATP: Km

FGFR1

MeO

OMe

NNH

NHO

N

N


20

MeO OMe

N

NH

NH

O

N

NRat heps

Clint (l/min/106)

Human hepsClint

(l/min/106)

MDCK AtoB pApp (cm/s)

MDCK BtoA pApp (cm/s)

60 8.1 10.5 x10-6 12.2 x10-6

In vivo PK

Species (media)

Cl (ml/min/kg)

Vss (l/kg)Oral

bioavailability (%)

Rat (plasma) 46 3.9 50

Dog (blood) 12 1.3 30

Main site of metabolism identified as terminal NMe of piperidine:Oxidative demethylation and N-oxidation

Models of metabolism Models of absorption

Pyrazolylbenzamide SAR: piperazine variation

21

X

MeO

OMe

NNHNH

O

Het

Cpd X HetFGFR1

enzyme IC50 (nM)

pFGFR1 cell assay IC50 (nM)

LogDpH7.4

Aq. Sol.pH7.4 (M)

13 CH2 0.7 19 3.1 27

14 O 0.9 6 3.2 1.4

16 CH2 0.9 17 1.8 37

17 O 1.7 17 1.9 56

18 CH2 1.6 11 2.3 372

N

N

N

N

N

NH

NH

N

N

Solvent


22

MeO

OMe

NNH

NHO

N

N

23

Cpd pKaMDCK

AtoB pApp (cm/s)

Rat hepsClint

(l/min/106)

Rat Cl (ml/min/kg) #

Rat Vss (l/kg) #

Rat oral bioavail. (%) #

13 7.6 10.5 x10-6 60 46 3.9 50

14 7.6 * 7.3 x10-6 75 - - -

16 8.6 4.1 x10-6 12 23 5.6 3

17 9.1 4.2 x10-6 7.2 7.8 1.8 4

18 9.2 5.2 x10-6 <3.9 59 11.7 16

X

MeO

OMe

NNHNH

O

Het

Pyrazolylbenzamide SAR: piperazine variation

N

NHet groups 13 & 14 16 N

NH

17NH

N18

N

Pyrazolylbenzamide summary and next steps…..

24

Representative compounds in the pyrazolylbenzamide series fall into two groups:-

•Those with moderate/high clearance and reasonable bioavailability,

• associated with lower pKa, higher LogD and higher permeability

and

•Those with low clearance but with low oral bioavailability,

• associated with higher pKa, lower LogD and lower permeability.

Pyrazolylbenzamide summary and next steps…..

25

Hypothesis• Metabolism appears to be blocked by protonation of the terminal

nitrogen. Higher pKa compounds show lower intrinsic clearance.

• However compounds with higher pKa, lower LogD, and/or higher NH donor count appear to show poor absorption.

Proposal• Explore N-alkyl heterocycle with moderated pKa and LogD.

(increased pKa and lower LogD).

• Explore NH heterocycles with increased lipophilicity and potential to sterically “mask” the polar NH group.

Optimal pyrazolylbenzamides

26

CpdFGFR1 enzyme

IC50 (nM)pFGFR1 cell

assay IC50 (nM)LogDpH7.4

Aq. Sol. pH7.4 (M)

pKa

19 0.2 12 2.4 157 8.5

20 0.5 12 3.0 * 148 8.7

CpdRat heps

Clint (l/min/106)Human heps

Clint (l/min/106)Rat PK

mediumRat Cl

(ml/min/kg)Rat Vss

(l/kg)Rat oral

bioavail. (%)

19 11 <6.1 plasma 16 3.4 54

20 9.7 <4.1 blood 13 1.7 46

* Estimated

Cpd 19 Cpd 20

MeO

OMe

NNH N

H

O

Het

NNH N O

Het =

Optimal pyrazolylbenzamides

27

MeO

OMe

NNH N

H

O

NNH

Compound 19 was selected for progression to clinical development and given the development code AZD4547

AZD4547 Discovery Synthetic Route

28

O

O

N

NH

NHO

N

NH

O

O

N

N

NH2

O

O

O

N

NH

O

N

O

O

O

O

O

O

O

N

O

O

NH

N

NH2

O O

F

NH

NH

NaHMDSTHF

+NaHToluene

NH2NH2

EtOH

(BOC)2OCH2Cl2

+

heat,DMSO


29

O

O

N

NH

NHO

N

NH

O

O

N

N

NH2

O

O

O

N

NH

O

N

O

O

O

O

O

O

O

N

O

O

NH

N

NH2

O O

F

NH

NH

NaHMDSTHF

+NaHToluene

NH2NH2

EtOH

(BOC)2OCH2Cl2

+

heat,DMSO


30

O

O

N

NH

NHO

N

NH

O

O

N

N

NH2

O

O

O

N

NH

O

N

O

O

O

O

O

O

O

N

O

O

NH

N

NH2

O O

F

NH

NH

NaHMDSTHF

+NaHToluene

NH2NH2

EtOH

(BOC)2OCH2Cl2

+

heat,DMSO

31

AZD4547 Characterization

FGFR1 FGFR2 FGFR3 FGFR4 KDR IGFR

Enzyme

IC50 (nM)0.2 2.5 1.8 165 24 581

Cell IC50 (nM) 13 2 40 142 258 829

• AZD4547 is a potent and selective inhibitor of FGFR 1, 2 and 3 receptor tyrosine kinases

32

Drug properties

Parameter AZD4547

Mol. Weight 463.6

Aq solubility (μM) 157

LogD 2.4

Form Crystalline, stable

Protein binding (% free; mouse, rat, rabbit, dog, human) 0.7,1.8, 0.3, 2.9, 2.1

Blood clearance (ml/min/kg; rat, dog) 39, 13

Blood Vdss (l/kg; rat, dog) 6, 5

Bioavailability (%; rat, dog) 42–100

In vitro hepatocyte clearance (ml/min/106 cells; rat, dog, human) 12, <4.4, ≤8.6

CYP inhibition IC50 (μM at 1A2, 2A6, 2E1, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4)

All >10

Ames Negative

Mouse lymphoma Negative

hERG (M) >33

33

Genetic dysregulation of FGFR confers sensitivity to AZD4547 in tumor cell lines

KG

1a

Su

m5

2-P

E

KM

S1

1

kDa

76-

52-

150-

102-

225-

52-

38-

31-

150-

102-

225-

MC

F7

FGFR1

FGFR2

GAPDH

FGFR3

Tumor cell line

Deregulated FGFR member/mechanism

Proliferation

IC50 (μM)SEM

KG1a FGFR1 – Gene fusion 0.018 (n=3) 0.0017

SUM52-PE

FGFR2 – Gene amplification

0.041 (n=4) 0.0185

KMS11FGFR3 – Translocation (t4;14) and mutation (Y373C)

0.281 (n=5) 0.0294

MCF7 None >30 (n=6) NA

34

• Dose-dependent antitumor activity at well tolerated doses

• Maximum efficacious doses – 12.5 mg/kg qd/6.25 mg/kg bid

• Efficacy is linked to to AUC rather than CMAX

12.5 mg/kg qd

6.25 mg/kg qd

3 mg/kg qd

3 mg/kg bid

6.25 mg/kg bid

Control

NS

–53%***

–70%***

–98%***–100%***

0 5 10 15 20 250.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

2.2

2.4M

ea

n T

um

ou

r vo

lum

e (

cm3

) +

/- S

EM

Days of Treatment

Control AZD4547 12.5mg/kg qd AZD4547 6.25mg/kg qd AZD4547 6.25mg/kg bid AZD4547 3mg/kg qd AZD4547 3mg/kg bid

Mea

n tu

mo

r vo

lum

e (c

m3)

± S

EM

AZD4547 induces dose-dependent efficacy in the KMS-II multiple myeloma xenograft model

35

AZD4547 reverses a bFGF driven angiogenic phenotype

Control media bFGF (5 ng/ml)

bFGF (5 ng/ml) + AZD4547 (100 nM)

Vessel formation in vitro

0

0.1

0.2

0.3

0.4

0.5

0.6

Control bFGF (1 μg/ml)

bFGF +AZD4547

(6.25 mg/kg bid)

MV

D p

er 5

000

μm

2

Vessel formation in vivo

Matrigel plug assay – mean vessel density

36

AZD4547 in vivo tumor efficacy is not attributable to inhibition of KDR

Tumor model

Dose (mg/kg)

Frequency of dosing

Inhibition of tumor growth

(%)

Calu-6 6.25 bid 0

LoVo 6.25 bid 0

HCT-15 6.25 bid 4.7

AZD4547 is inactive in KDR-sensitive xenograft models

AZD4547 has no effect on vessel growth in KMS11 tumors

Control AZD4547(7 days at 6.25 mg/kg bid)

CD31 Staining

Calu-6

–2 0 2 4 6 8 10 12 14 16 18

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

Mea

n t

um

or

volu

me

(cm

3 ) ±

SE

M

Days of treatment

Control

Cediranib 3 mg/kg qd

AZD4547 6.25 mg/kg bid

37

FGFR2 gene amplified gastric cancer cells are very sensitive to AZD4547

Sensitivity of gastric cancer cells to AZD4547 in MTS assay

100

0.01

1

0.001

0.1

10

GI 5

0 (

μM

)

GC lines

38

AZD4547 causes dose-dependent tumor growth inhibition in Snu-16 gastric xenograft model

• Dose-dependent antitumor efficacy of AZD4547 at well tolerated doses

• Evidence of tumor regression at 12.5 mg/kg qd

• Efficacy of AZD4547 is greater in the Snu-16 model than in gastric cancer xenograft models with normal FGFR2 gene copy number (FISH = 1)

Model

FGFR2 expression % TGI by AZD4547

FISH Affy12.5

mg/kg qd25

mg/kg qd

Snu-16 6 +++ > 100 N/A

AZ521 1 +++ 63 77

MGC803 1 +++ 45 72

1000

0

Treatment period (day)

800

3

600

400

6 10 13 17 20 24 27

AZD4547 1.56 mg/kg qd po


Tu

mo

r vo

lum

e (m

m3 )

0



200

Vehicle control

AZD4547 is significantly more efficacious in gastric cancer primary models with FGFR2 gene amplification

39

GC model ID SGC100 SGC031 G009 SGC001 G001 SGC020 SGC002 SGC110 SGC105 SGC083

FGFR2 FISH score

1Disomy

2Trisomy

3Trisomy

3Trisomy

4Poly-somy

5 Poly-somy

5Poly-somy

5Poly-somy

5Poly-somy

6Gene

Amplifi-cation

FGFR2 FISH GCN

1.8 2.2 2.6 2.6 3.3 2.6 3.6 4 4.9 30

Western Blot ++ + + +++ + + + ++ + ++++++

In vivo %TGI (25mg/kg/qd)

26(P=0.030)

7(P=0.419)

44(P=0.004)

98(P=<0.0001)

76(P=<0.00

01)

25(P=0.143)

26(P=0.053)

14(P=0.120)

10(P=0.288)

162(P=<0.0001)

AZD4547 is efficacious against FGFR1-amplified squamous cell lung cancer primary models.

40

FGFR1 IHC (IHC score embedded)

Score 6

L123 LC038 LC026 LC036

+++

+++

+++

-ve

Score 6

Score 6

Score 1

FGFR1 FISH (FISH score embedded)

Model ID:

0

200

400

600

800

1,000

1,200

0 2 4 6 8 10 12 14

Tu

mo

r vo

lum

e/m

m^3

)

Treatment period (days)

Efficacy study of AZD4547 in L123

G1: Vehicle control

G2: AZD4547 25 mg/kg/qd

0

200

400

600

800

1,000

1,200

0 2 4 6 8 10 12 14

Tu

mo

r vo

lum

e/m

m^3

)


Efficacy study of AZD4547 in L123

G1: Vehicle control

G2: AZD4547 25 mg/kg/qd

0

200

400

600

800

1,000

1,200

0 7 14 21 28

Tum

or V

olum

e (m

m3)

Treatment period (Days)

Efficacy study of AZD4547 in LC038

Vehicle controlAZD4547 25mg/kg/qd p.o

0

200

400

600

800

1,000

1,200

0 7 14 21 28

Tum

or V

olum

e (m

m3)

Treatment period (Days)


Vehicle controlAZD4547 25mg/kg/qd p.o

0

200

400

600

800

1,000

1,200

0 2 4 6 8 10 12 14 16 18 20 22

Tu

mo

r V

olu

me

(mm

3)



G1: Vehicle control

G2: AZD4547 25mg/kg/qd

0

200

400

600

800

1,000

1,200

0 2 4 6 8 10 12 14 16 18 20 22

Tu

mo

r V

olu

me

(mm

3)



G1: Vehicle control

G2: AZD4547 25mg/kg/qd

0

100

200

300

400

500

600

700

800

900

1000

0 3 6 9 12 15 18 21

Tum

or V

olu

me

(mm

3)

Treatment Period (days)

AZD4547 TGI in LC022F8

G1: vehicle control

G2: AZD4547: 25mg/kg

0

100

200

300

400

500

600

700

800

0 3 6 9 12 15 18 21

Tum

or V

olu

me

(mm

3)



G1: vehicle controlG2: AZD4547: 12.5mg/kgG3: AZD4547: 25mg/kg

0

100

200

300

400

500

600

700

800

900

0 3 6 9 12 15 18 21

Tum

or V

olu

me

(mm

3)




0

100

200

300

400

500

600

700

800

900

1000

0 3 6 9 12 15 18 21

Tum

or V

olu

me

(mm

3)



G1: vehicle control

G2: AZD4547: 25mg/kg

0

100

200

300

400

500

600

700

800

0 3 6 9 12 15 18 21

Tum

or V

olu

me

(mm

3)




0

100

200

300

400

500

600

700

800

900

0 3 6 9 12 15 18 21

Tum

or V

olu

me

(mm

3)




41

Summary

• Pyrazolylaminopyrimidine hits provided key understanding of SAR and binding interactions leading to potent and selective inhibitors.

• The discovery of pyrazolylbenzamide leads provided a series with more attractive physical properties for optimisation of vivo activity.

• The design of pyrazolylbenzamide with the appropriate balance of pKa, lipophilicity and polarity lead to potent FGFR inhibition in vivo and the identification of AZD4547.

• AZD4547 is a potent, orally bioavailable inhibitor of FGFR tyrosine kinases 1, 2 and 3.

• AZD4547 is selective versus a number of off-target kinases including KDR and has favourable drug properties.

• Genetic dysregulation of FGFRs confers sensitivity to AZD4547 in tumour cell lines and primary, ex-plant tumour models

• AZD4547 is currently in Phase I/II clinical trials

42

Paul GavineQunsheng JiXinying Su

Katherine YeLucy Yin

Jingchuan ZhangLiang XieMin Shi

Jessie XuDavid Zhang

Qiuli GuoShirley ZhangMaggie Wang

Alderley Park UK

Andy ThomasMaria-Elena Theoclitou

David ButtarLinette RustonGail WrigleyMike DennisDavid Rudge

Tanya ColemanRobin SmithPaul Gavine

Teresa KlinowskaLorraine Mooney

Neil SmithDawn BakerNigel Brooks

AcknowledgmentsLO Discovery Translational science

Alderley Park UK

Andrew Leach Richard Norman

Anne-Kathrin SchottJason BreedKevin Foote

Andrew GarnerDerek Ogg

Jonathon OrmeJennifer Pink

Karen Roberts

LG Discovery

Frances WangLin Zhang

Ming LiShuQiong Fan

Kunji Liu Zhengwei Dong Guanshan Zhu

Lili Tang

Alderley Park UK

Elaine KilgourPaul Smith

Innovation Centre China

43 Andy Thomas | 22 May 2012 R&D | Oncology iMed

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the discovery of azd4547

Science

fgfr tyrosine kinase

pyrazolylaminopyrimidines

inhibitors of fgfr1

fgfr driven effects

identification of az

colorectal cancer

kinase domains

sar analysis