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University of MilanoBicocca, Monza, Italy
Incidence of Incidence of HematologicHematologic MalignanciesMalignancies
Type of LeukemiaType of Leukemia Incidence per Incidence per 100,000*100,000*
Overall Overall 66––1010CMLCML 11––22CLLCLL 22––33AMLAML 22––33ALLALL 11––22
University of MilanoBicocca, Monza, Italy
Men 290,890
Women 272,810
26%26% Lung and bronchusLung and bronchus
15%15% BreastBreast
10%10% Colon and rectumColon and rectum
6%6% PancreasPancreas
6%6% OvaryOvary
4%4% LeukemiaLeukemia
3%3% NonNon--HodgkinHodgkin’’s lymphomas lymphoma
3%3% Uterine corpusUterine corpus
2%2% Brain/nervous systemBrain/nervous system
2%2% Multiple myelomaMultiple myeloma
22%22% All other sitesAll other sites
Lung and bronchus 33%
Prostate 10%
Colon and rectum 10%
Pancreas 5%
Leukemia 4%Non-Hodgkin’s lymphoma 4%
Esophagus 4%
Liver/intrahepatic bile duct 3%
Urinary bladder 3%
Kidney 3%
All other sites 21%
Leukemia Comprises a Vast Leukemia Comprises a Vast Proportion of Cancer Deaths in the Proportion of Cancer Deaths in the
United StatesUnited States
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Incidence and Mortality Associated With Incidence and Mortality Associated With Leukemias (United States, 2003)Leukemias (United States, 2003)
Incidence Mortality
OverallAMLCLLCMLALL
35,000
30,000
25,000
20,000
15,000
10,000
5000
0
35,000
30,000
25,000
20,000
15,000
10,000
5000
0
33,440
11,920
8,190
4,600 3,830
23,300
8,870
4,800
1,570 1,450
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University of MilanoBicocca, Monza, Italy
Courtesy of John K. Choi, MD, PhD, University of Pennsylvania.
Normal Chronic Phase CML
Comparative Peripheral Blood SmearComparative Peripheral Blood Smear
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University of MilanoBicocca, Monza, Italy
Table 46.2-1 Diagnosis and Evaluation of Acute Leukemia-------------------------------------------------------------------
Symptoms
Fatigue, malaise, dyspneaEasy bruisability, weight loss
Bone pain or abdominal pain (less common)Neurologic symptoms (rare)
SignsAnemia and pallor
Thrombocytopenia, hemorrhage, ecchymoses, petechiae, fundal hemorrhage
Fever and infection (pneumonia, sepsis, perirectal abscess)Adenopathy, hepatosplenomegaly, mediastinal mass
Gum or skin infiltration (rare)Renal enlargement and insufficiency (rare)
Cranial neuropathy (rare)
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Clinical Presentation of CMLClinical Presentation of CML
Common SymptomsCommon Symptoms Common SignsCommon SignsFatigueFatigue Palpable Palpable splenomegalysplenomegalyWeight loss/anorexiaWeight loss/anorexiaAbdominal fullnessAbdominal fullness
Common Laboratory FindingsCommon Laboratory FindingsAbnormal differentialAbnormal differential AnemiaAnemiaLeukocytosisLeukocytosis BasophiliaBasophiliaThrombocytosisThrombocytosis
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LEUCEMIA MIELOIDE CRONICA
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University of MilanoBicocca, Monza, ItalySawyers. N Engl J Med. 1999;340:1330.
Faderl et al. Ann Intern Med. 1999;131:207.
Epidemiology of CMLEpidemiology of CML
Median age range at presentation is Median age range at presentation is 4545--55 years55 yearsIncidence increases with ageIncidence increases with age-- Up to 30% of patients are aged >60 years Up to 30% of patients are aged >60 years
Slightly higher incidence in malesSlightly higher incidence in males-- MaleMale--toto--female ratiofemale ratio——1.3:11.3:1
At presentationAt presentation-- 50% diagnosed by routine laboratory tests50% diagnosed by routine laboratory tests-- 85% diagnosed during chronic phase85% diagnosed during chronic phase
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Courtesy of John K. Choi, MD, PhD, University of Pennsylvania.
Normal Chronic Phase CML
Comparative Peripheral Blood SmearComparative Peripheral Blood SmearAcute Leukemia
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PATOGENESI
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University of MilanoBicocca, Monza, Italy
CytogeneticCytogenetic Abnormality of CML:Abnormality of CML: The Philadelphia ChromosomeThe Philadelphia Chromosome
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The Philadelphia Chromosome: The Philadelphia Chromosome: t(9;22) Translocationt(9;22) Translocation
22
bcr
abl
Ph
bcr-abl
FUSION PROTEIN WITH TYROSINE KINASE ACTIVITY
9 9+
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Chromosome Chromosome in in HematologicHematologic MalignanciesMalignancies
LeukemiaLeukemia % of Ph+ Patients% of Ph+ Patients
CMLCML 95 95
ALL (Adult)ALL (Adult) 1515––3030
ALL (Pediatric)ALL (Pediatric) 55
AMLAML 22Faderl S et al. Oncology (Huntingt). 1999;13:169-184.
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bcrbcr--ablabl Gene and Fusion Protein Gene and Fusion Protein Tyrosine Tyrosine KinasesKinases
Adapted from Melo JV. Blood. 1996;88:2375-2384.
p210 Bcr-Abl
p185 Bcr-Abl2-11
2-11
Chromosome 9c-bcr
Chromosome 22
c-abl
Exons
Introns
CML Breakpoints
ALL Breakpoints
1
2-11
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p210p210BcrBcr--AblAbl Fusion Protein Tyrosine Fusion Protein Tyrosine KinaseKinase
Faderl S. N Engl J Med. 1999;341:169.
Extracellular space
Y177
BAP-1 GRB2
Cytoplasm
SH3 SH2 SH1
CBL SHC CRKL
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BcrBcr--AblAbl Signal Transduction Signal Transduction PathwaysPathways
Adapted from Pasternak G et al. J Cancer Res Clin Oncol. 1998;124:643-660.
Bcr-Abl
BCL 2inhibition of apoptosis
MYC GRB2 CRKL CBL (p120CBL)
RAS
RAF-MEK-MAPK cascaderegulates cell cycle progression and differentiation
activates
JAK/STATs
upregulation of
Paxillin (Adhesion) PI-3 kinase
Actin (Adhesion)
β-catenin is constitutively tyrosine (Y)-phosphorylated and associated to Bcr-Abl in human CML cells
nonpS/Tβ-cat
- + - + imatinib 2hCML m KU812IP:α β-cat
97 kDa
97 kDa β-cat
210 kDa Bcr-Abl
97 kDa p-Y-β-cat
imatinib prevents tyrosine (Y)-phosphorylation of β-catenin and accumulation of its transcriptional
competent pool which is serine/threonine (S/T)-nonphosphorylated
- + - + imatinib 210 kDa
97 kDa
Bcr-Abl
β-cat210 kDa p-Y-Bcr-Abl
IP:α Abl CML m KU812
97 kDa nonpS/Tβ-cat
97 kDa p-Y-β-cat
2h
Characteristics of CML Patient Samples
Pt. Age Type CML phase %blasts1 58 BM BC 30% 2 43 BM BC 73% 3 37 BM BC 37% 4 74 BM BC 54% 5 45 BM BC 96% 6 58 BM BC 58%
BM, bone-marrow mononuclear cells; BC, blast crisis
Ls174tKU812
CML 1CML 2
CML 3CML 4
CML 5CML 6
β-cat
Bcr-Abl210 kDa
97 kDa
97 kDa p-Y-β-cat
IP:α β-cat
Ls174t = human colorectal cancer cell line used as negative control for Bcr-AblKu812 = BC-CML-patient established cell lineCML 1 - 6 = fresh bone-marrow mononuclear cells from BC-CML-patients
Proposed mechanism:
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University of MilanoBicocca, Monza, Italy
University of MilanoBicocca, Monza, Italy
University of MilanoBicocca, Monza, Italy
University of MilanoBicocca, Monza, Italy
DIAGNOSI
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Clinical Presentation of CMLClinical Presentation of CML
At presentation:At presentation:
50% diagnosed by routine 50% diagnosed by routine laboratory testslaboratory tests
85% diagnosed during chronic 85% diagnosed during chronic phasephase
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Clinical Presentation of CMLClinical Presentation of CML
Common SymptomsCommon Symptoms Common SignsCommon SignsFatigueFatigue Palpable Palpable splenomegalysplenomegalyWeight loss/anorexiaWeight loss/anorexiaAbdominal fullnessAbdominal fullness
Common Laboratory FindingsCommon Laboratory FindingsAbnormal differentialAbnormal differential AnemiaAnemiaLeukocytosisLeukocytosis BasophiliaBasophiliaThrombocytosisThrombocytosis
University of MilanoBicocca, Monza, Italy
Common laboratory findingsCommon laboratory findings-- Abnormal differentialAbnormal differential-- LeukocytosisLeukocytosis-- ThrombocytosisThrombocytosis-- AnemiaAnemia-- BasophiliaBasophilia
Faderl et al. Ann Intern Med. 1999;131:207.Goldman. Curr Opin Hematol. 1997;4:277.
Clinical Presentation of Clinical Presentation of Chronic Phase CMLChronic Phase CML
Asymptomatic in ~50% of casesAsymptomatic in ~50% of casesCommon symptomsCommon symptoms-- FatigueFatigue-- Weight loss/anorexiaWeight loss/anorexia-- Abdominal fullnessAbdominal fullness
Common signsCommon signs-- Palpable splenomegalyPalpable splenomegaly
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Typical Laboratory Parameters Typical Laboratory Parameters by Phase of CMLby Phase of CML
ParameterParameter ChronicChronic AcceleratedAccelerated BlasticBlasticWBC countWBC count >>20 x 1020 x 1099/L/L —— ——BlastsBlasts 3%3%––10%10% >>15% 15% >>30%30%
BasophilsBasophils ↑↑ >>20% 20% ——PlateletsPlatelets ↑↑or normalor normal ↓↓ or or ↑↑ ↓↓
Bone marrowBone marrow Myeloid hyperplasia Myeloid hyperplasia CytogeneticsCytogenetics Ph+Ph+BcrBcr--AblAbl ++ ++ ++
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Clinical Course: Phases of CMLClinical Course: Phases of CML
Chronic phase
Median 4–6 years stabilization
Accelerated phase
Median duration up to 1 year
Blastic phase (blast crisis)
Median survival 3–6 months
Terminal phase
Advanced phases
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University of MilanoBicocca, Monza, Italy
Nucleo Ph+
Nucleo normale
Metafase Ph+
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University of MilanoBicocca, Monza, Italy
M
692 bp501 bp
Patie
nt E
.L.
BaF
3-T/
P
CNeg
ativ
e Pa
tient
TMHLH TKD
308 bp
533 bp
B.
C.
501 bp692 bp
M 10-1 10-2 10-3 10-4 10-5 10-6 CU
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University of MilanoBicocca, Monza, Italy
TERAPIA
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The Ideal Target for Molecular The Ideal Target for Molecular Therapy Therapy
Present in the majority of patients with a Present in the majority of patients with a specific diseasespecific disease
Determined to be the causative Determined to be the causative abnormalityabnormality
Has unique activity that isHas unique activity that is
-- Required for disease inductionRequired for disease induction
-- Dispensable for normal cellular functionDispensable for normal cellular function
Courtesy of BJ Druker, MD.
University of MilanoBicocca, Monza, Italy
BcrBcr--AblAbl as a Therapeutic Target for CMLas a Therapeutic Target for CML
BcrBcr--AblAbl is detected in 95% of patients is detected in 95% of patients with CMLwith CML
BcrBcr--AblAbl is the causative abnormality of is the causative abnormality of CMLCML
BcrBcr--AblAbl tyrosine tyrosine kinasekinase is constitutively is constitutively activated activated intracellularlyintracellularly-- Tyrosine Tyrosine kinasekinase activity is required for CML activity is required for CML
cell functioncell function
Therapy of CML: Response Criteria
Disappearance of splenomegalyNormal physical exam
Hematologic Response Cytogenetic Response
Complete: Major:Normal peripheral blood count Complete: 0% Ph+ cells
WBC <10 x 109/L Partial: 1%–34% Ph+ cellsPlatelets <450 x 109/L Minor: 35%–95% Ph+ cellsNo immature cells
Ph+=Philadelphia chromosome-positive.
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IMATINIB IMATINIB
Tyrosine Tyrosine KinaseKinase InhibitorInhibitorfor CMLfor CML
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Structure Structure of imatinibof imatinib
Class: Class: PhenylaminopyrimidinesPhenylaminopyrimidines, 589.7 mw, 589.7 mw
CH3 SO3 H
O
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BcrBcr--AblAbl––Positive and Positive and ––Negative Cell Negative Cell LinesLines
Adapted from Gambacorti-Passerini C et al. Blood Cells Mol Dis. 1997;23:380.
*Bcr-Abl-negative cell lines†Bcr-Abl-positive cell lines
U937*KG1*KCL22*K562†
KU812†
SU DHL1†
STI571 Concentration (μM)
% Control CPM
0 0.1 0.3 1 3 10
0
20
40
60
80
100
120
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University of MilanoBicocca, Monza, Italy
LAMA84 Control
LAMA84 24h 1uM
LAMA84 44h 1 uM
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University of MilanoBicocca, Monza, Italy
0
1
2
3
4
5
6
7
8
9
0 10 20 30 40
days
tumor weight mg x 1000 ctrl
2x50 mg/kg i.p.
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0
20
40
60
80
100
120
140
ctrl 6h 7h 20h 21h 30h 30htime of drug exposure
% c
pm
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bcr/abl
bcr/abl
anti-phosphotyrosine
anti-abl
i.p. 2h p.o. i.p. 5h p.o. i.p. 9h p.o.
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0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
0 5 10 15 20
days
tumor weight mg x 1000
ctrl3x160 mg/kp p.o.
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0102030405060708090
100
0 10 20 30 40 50days
tumor free survival
ctrl3x50 mg/kg i.p.3x160 mg/kg p.o.
University of MilanoBicocca, Monza, Italy
Chronic Phase patients
30.00
20.00 23.08
45.16
32.0028.57
44.83
30.00
96.77
76.9280.00
70.0073,68
54.84 55.17
71.43 68.00
3.230.00
20.00
40.00
60.00
80.00
100.00
0 3 6 9 12 15 18 21 24
Therapy, month
% p
atie
nts
% pt without response % pt with major or complete response
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University of MilanoBicocca, Monza, Italy
University of MilanoBicocca, Monza, Italy
University of MilanoBicocca, Monza, Italy
MCyR within <=3 mthsMCyR within >3-6 mthsMCyR within >6-12 mthsMCyR later than 12 mths
= Censored observations
% w
ithou
t los
s of
MC
yR
0102030405060708090
100
Months since MCyR0 6 12 18 24 30 36 42 48 54 60 66
University of MilanoBicocca, Monza, Italy
Annual Event Rates in Patients Annual Event Rates in Patients onon FirstFirst--line Imatinibline ImatinibYear after
achieving CCyR All events* AP/BC1st 3.3% 1.5%
2nd 7.5% 2.8%3rd 4.8% 1.6%4th 1.5% 0.9%5th 0.9% 0.6%
* All deaths or loss of response* All deaths or loss of response includingincluding progression to AP/BCprogression to AP/BC
University of MilanoBicocca, Monza, Italy
University of MilanoBicocca, Monza, Italy
Decreasing residual leukemia
Num
ber of leukemia cells (log
10 )
0
1
2
3
4
5
6
7
8
9
10
11
12
13
0
6.0
5.0
4.0
3.0
1.0
0
Log
redu
ctio
n fr
om b
asel
ine Leukocytosis
RQ-PCR positive
RQ-PCR negative
Ph-chromosome pos
Ph-negative but…
Cure ?
BCRBCR--ABL transcript numbers expressed as ABL transcript numbers expressed as log reduction in patients responding to treatmentlog reduction in patients responding to treatment
2.0
University of MilanoBicocca, Monza, Italy
University of MilanoBicocca, Monza, Italy
University of MilanoBicocca, Monza, Italy
Clinical Course: Phases of CMLClinical Course: Phases of CML
Chronic phase
Median 4–6 years stabilization
Accelerated phase
Median duration up to 1 year
Blastic phase (blast crisis)
Median survival 3–6 months
Terminal phase
Advanced phases
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University of MilanoBicocca, Monza, Italy
Degree of Degree of BCRBCR--ABLABL log reduction in 124 log reduction in 124 CCyRCCyR pts at 1 and 4 yearspts at 1 and 4 years (in percent)(in percent)
39
12
31
39
41
8
22
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Year 1 Year 4
>= 4 log reduction
3 - < 4 log reduction
2 - < 3 log reduction
< 2 log reduction
8
Carlo Gambacorti-Passerini
Lo studio ILTE
(Imatinib Long Term Effects)
z
REL - CML, 15/04/2010, MILANO
z
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University of MilanoBicocca, Monza, Italy
HR
MUD ALLO
LR
NR R
α -IFN
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University of MilanoBicocca, Monza, Italy
BMT activity for CML in Eurolandia
0
200
400
600
800
1000
1200
1400
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
total
V.U.D.
University of MilanoBicocca, Monza, Italy
University of MilanoBicocca, Monza, Italy
RESISTENZA
Recidiva ematologica, citogenetica (>10%) o aumento confermato di >5 volte in PCR.
University of MilanoBicocca, Monza, Italy
Cytogenetic and hematological response of patient 506
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7 8 9 10 11 12Therapy, month
% of Ph+ cells WBC (* 1000) % of blasts PLT(*1000)
ASH 2007
Duration of major cytogenetic response
Dasatinib in blast phase CML
Progression was defined as loss of major or minor HR, or no decrease in blasts (PB or BM) from baseline within 4 weeks of maximum dasatinib dose; patients who underwent SCT were censored
Prop
ortio
n no
t pro
gres
sed
1.0
0.8
0.6
0.4
0.2
00 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Months
n No. progressedMedian
(months)Myeloid blast 36 15 16.8Lymphoid blast 25 18 4.1
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University of MilanoBicocca, Monza, Italy
IIIIII Amplification of BCR/ABLAmplification of BCR/ABL
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0
20
40
60
80
100
120
0 0,1 0,3 1 3 10
STI571 (µM)
% C
ontr
ol
LAMA84
LAMA84R
University of MilanoBicocca, Monza, Italy
University of MilanoBicocca, Monza, Italy
LAMA84 LAMA84RSTI571(µM) - 1 3 10 - 1 3
bcr/ablAnti-phospho
Tyrosine
Anti-actin Actin
1010
University of MilanoBicocca, Monza, Italy
University of MilanoBicocca, Monza, Italy
University of MilanoBicocca, Monza, Italy
University of MilanoBicocca, Monza, Italy
Pt 010/12_01Pt 010/12_01
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Tas(22q11)
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Tas(22q11)
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IVIV Mutations of BCR/ABLMutations of BCR/ABL
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University of MilanoBicocca, Monza, Italy
University of MilanoBicocca, Monza, Italy
„„onon““ state (active)state (active)„off“ state (inactive)
IRK3P
IRK
F1007
Y1162
R1155
Abl:STI571
Y253
Y393
R386
Y1162
F1007
Hck:PP1
F278
R409Y416
Abl:PD173955
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University of MilanoBicocca, Monza, Italy
University of MilanoBicocca, Monza, Italy
T315I
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Abl w.t.: prospettiva 2
University of MilanoBicocca, Monza, Italy
Abl T315I: prospettiva 2 (la freccia indica il residuo di Ile315)
University of MilanoBicocca, Monza, Italy
University of MilanoBicocca, Monza, Italy
University of MilanoBicocca, Monza, Italy
University of MilanoBicocca, Monza, Italy
D276
E279
K274
R386
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CONFORMATION
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Molecular structures and Molecular structures and biological databiological data
N
NON
NH
NC O
O
ClClDasatinibBosutinib
DasatinibDasatinib SKISKI--606606
rr--AblAbl 0.3 0.3 nMnM 2.6 nM2.6 nM
Table below shows the IC50 values of these two kinase inhibitors.
University of MilanoBicocca, Monza, Italy
Bosutinib: A Dual Inhibitor of Srcand Abl Kinases
Boschelli et al. J Med Chem. 2005;48:3891-3902.Golas et al. Cancer Res. 2003;63:375-381.Golas et al. Cancer Res. 2005;65:5358-5364.
N
C N
H N
C l C l
O
O
ON
N
Src Enzyme (Elisa) IC50 = 1.2 nMSrc Enzyme (Lance) IC50 = 3.8 nMAbl Enzyme IC50 = 1.4 nM
K562 Cell IC50 = 20 nM KU812 Cell IC50 = 4.3 nM
Puttini et al. Cancer Res 2006; 66: 11314-22Courtesy of L Scapozza and A Shaheen, University of
Geneva, Switzerland
Published Ahead of Print on December 15, 2008 as 10.1200/JCO.2008.19.8853The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2008.19.8853
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