A seminar given to Chromocell based on the discovery of dasatinib.

1. PAGE 1
Gengcheng Yang
April 20, 2012
Lab Meeting

2. PAGE 2
Starting Point: Target Selection
• Among many kinases, which one to select?
Human Kinome, ~5000
Human Genome, more complex
• Selectivity among the kinase family members
• Multiple SAR

3. PAGE 3
Human Immune Response
Human immunity relies on the activation of
T-cells.
Once initiated, T-cell activation is amplified
by sequential activation of three distinct
classes of nonreceptortyrosine kinases:
• Src family kinases (Lck and Fyn)
• Syk family kinases (Syk and ZAP-
70)
• Tec family kinases (Itk, Txk, and
Tec)
How about inhibiting some of these kinases?
Chen, P et al, J. Med. Chem. 2006, 49, 6819-6832
Figure 1. Schematic diagram of T-cell receptor (TCR)
activation by antigen presenting cell (APC)--- major
histocompatibility peptide (MHC) complex.

4. PAGE 4
Target Discovery and Validation
➢ The c-Src proto-oncogene plays a major role in the development, growth, progression,
and metastasis of a wide variety of human cancers. Src activation, in the form of elevated
kinase activity and/or protein expression levels, has been demonstrated in several major
cancer types, including colon, breast, pancreatic, lung, and brain carcinomas.
➢ Lck is a validated potential immuno-suppressive molecular target
➢ An Lck inhibitor should inhibit T-cell activation leading to the treatment of acute and
chronic T-cell mediated autoimmune and inflammatory disorders including:
• Rheumatoid arthritis (RA) , Psoriasis
• Leukemia, human colon carcinoma, small cell lung cancer, etc.
Genetics experimental results from Lck-/- mice:
➢ These mice display a SCID-like syndrome,unable to reject skin grafts despite the
presence of peripheral T-cells.
➢ Overexpression of a dominant negative form of Lck leads to early arrest of thymocyte
development prior to expression of CD4, CD8, and the TCR.
T. Wen et al, Eur. J. Immunology, 1995, 25, 3155-3159

5. PAGE 5
Discovery of A Pan-Src Inhibitor
murine Lck IC50 = 6.6 uM
human Lck IC50 = 5 uM
T-cell proliferation IC50 >10 uM
1 was identified as an ATP competitive Lck inhibitor
1. HTS (Filter binding assay ) of internal compound collection of BMS

6. PAGE 6
Initial Structure-Activity Relationship (SAR) Exploration
Chen, P et al, J. Med. Chem. 2006, 49, 6819-6832
➢ East: Investigated the importance of the
carboxanilide side chain on the thiazole
➢ West: Amide and carbamate exploration
found tert-butyl carbamate 5a was equipotent
and served as a starting point for optimization

7. PAGE 7
SAR West and the East, cont’d
Chen, P et al, J. Med. Chem. 2006, 49, 6819-6832
➢ East: Keep 2, 6-diMe or similar groups
➢ West: Further modification

8. PAGE 8
SAR North: Modification of substituents on thiazole-C4
J. Wityak et al., Bioorg. Med. Chem. Lett. 2003, 13, 4007–4010
➢ Results from benzothiazole series ( 11)
➢ PBL proliferation assay: 11d IC50 =
0.88 uM 11e IC50 = 1.8 uM
hLck (IC50 ) = 35 nM
N
S
H
N
OO
HN
Cl
11d

9. PAGE 9
Milestone and Questions about Amide, Carbamide and Urea Linkers
Chen, P et al, J. Med. Chem. 2006, 49, 6819-6832;
J. Wityak et al., Bioorg. Med. Chem. Lett. 2003, 13, 4007–4010
➢ Replacement of the cyclopropyl amide with an alkyl (7o),
cyclobutyl (7v) amide, or small alkyl substitution on the
cyclopropyl ring (7p,7q) leads to a substantial loss (>1000-
fold) in potency.
➢ Benzamide (7r), cyclopentyl amide (7w), 2-thienylamide
(7s) retains some of the intrinsic potency. Only 3-thienyl amide
7t displays comparable potency to 7n.
➢ T-cell proliferation assay, 7t (IC50 > 2 uM) is less potent
than 7n.
hLck (IC50 ) = 35 nM
N
S
H
N
OO
HN
Cl
11d (7n)
hLck (IC50 ) = 30 nM
N
S
H
N
OO
HN
HN
8c
Minor structural changes led to dramatic drops ( ~1000x)
in activity. Thus, a very narrow SAR pattern was observed
in this series.

10. PAGE 10
Model of Aminothiazole Binding to Lck
Chen, P et al, J. Med. Chem. 2006, 49, 6819-6832;
J. Wityak et al., Bioorg. Med. Chem. Lett. 2003, 13, 4007–4010
Figure4. Proposedbindinginteractions of thiazole 7n (white)
and benzothiazole 11 (blue) with the Lck kinase.
Figure5. Proposedbindingconformations
of 4-unsubstitutedand 4-Me thiazoles.
Critical H-bond interactions withthe Lckactive sites:
➢ The aniline is positionedfavorably for a productive H-bond interaction
with the Thr316 hydroxyl, and both the thiazole nitrogen and the
cyclopropyl carboxamide NH are in H-bond contact with the backbone
carbonyl and NH of Met319.
➢ The cyclopropyl groupfits snugly in a hydrophobic pocket.
➢ This binding mode is consistent withthe 2,6-aniline
di-substitution, which orients the phenyl ring so that it can fit into an
angular deep but narrow hydrophobic pocket.
➢ 4-Me thiazole cannot adopt the requiredbinding conformation.

11. PAGE 11
Heteroaryl Replacement of the 2-Carboxamides and
Identification of a Pan-Src inhibitor
Das, J. et al, Bioorg. Med. Chem. Lett. 2003, 13, 2587-90.
➢ In the exploratory SAR investigations with benzothiazole
series, replacement of the 2-NH-R with certain heteroaryl
amines led to highly potent inhibitors (13, 13a).
➢ Molecular docking of 7n (see last slide, Fig. 4) suggested
that the cyclopropyl amide carbonyl was not engaged in any
productive H-bond interaction.
➢ Could C2-carboxamide be replaced with a heteroaryl amine
that can function as a conformationally constrained “amide
mimetic”?
Figure 6. Activities of benzothiazoles 13 and 13a.
13a
hLck (IC50 ) = 20 nM
T-cell (IC50 ) = 640 nM
N
S
N
H
13
H
N
O
Cl
CH3
N
NH3C
CH3
N
S
N
H
H
N
O
Cl
OH
NN
H
HO
Log P: 5.62Log P: 6.94
Mol. Wt.: 423.92 Mol. Wt.: 455.92
hLck (IC50 ) = 0.5 nM
T-cell (IC50 ) = 450 nM
Further SAR on West:
Heteroaryl Replacement of
c-Pr-amide
hLck (IC50 ) = 35 nM
N
S
H
N
OO
HN
Cl
11d (7n)
2
6
1
1
2
3

12. PAGE 12
More SAR West: Heteroaryl Replacement on the West
Chen, P et al, J. Med. Chem. 2006, 49, 6819-6832
N
S
H
N
O
N
H
Cl
Het
2'-pyridyl amine (12a) increase potency (30-fold).
3'- and 4'-pyridyl (12b,12c) are 6-8-fold less potent vs. 2'-
isomer.
4' or 6' mono-, and 4',6'-diMe on pyridine ring (12j, k, l)
tolerated.
2',6'-di-Me-4'-pyrimidinyl-substituted analog(12m) was
identified as one of the more potent Lck inhibitors with
this adjustment.
12o with 2,4,6-tri-Me aniline on the east is slightly less
potent.
Regioisomeric pyrimidinyl analog (12n) is significantly
less potent (50-fold) than 12m.
2'-Cl-6'-Me aniline is
more favorable than
2',4',6'-tri-Me aniline
hLck (IC50 ) = 35 nM
N
S
H
N
OO
HN
Cl
11d (7n)
N
N
pyridazine
N
N
pyrazine
N
N
N
pyrimidine
pyridine
1
2
3
4
5
6

13. PAGE 13
Further West: Solubility Improvement and Discovery of 2 (Dasatinib)
N
S
H
N
O
N
H
ClN
N
12m
hLck (IC50 ) = 1 nM
T-cell (IC50 ) = 80 nM
N
S
H
N
O
N
H
ClN
N
N
2
hLck (IC50 ) = 0.4 nM
T-cell (IC50 ) = 3 nM
NHO
Log P: 4.64
Log P: 5.52
Further West:
Appending weakly
basic or polar group
improved aq.solubility
Polar groups on C6
boosts potency
1 2
4
6
BMS-354825
Chen, P et al, J. Med. Chem. 2006, 49, 6819-6832
Generic Name:
Dasatinib, after BMS Chemist Jagabandhu Das
(Haystack, Jan 26, 2012)

14. PAGE 14
Characterization of Most Potent Analogs: Binding Model
NH2
CH
C
OH
O
NH2
C
HO
O
OH
NH2
C
HHO
O
GlycineLeucine Tyrocine
Figure 7. Proposed binding interactions of 12m (left) and 2 (right) with the Lck kinase domain.
Van der waals surfaces are shown for 12m (left, inset).
Chen, P et al, J. Med. Chem. 2006, 49, 6819-6832
➢ 2-amino pyrimidine ring may occupy a narrow hydrophobic pocket delineated by Leu251,Tyr318
and Gly322.
➢ The significant increase in cellular potency of 2 and related analogs relative to 12m cannot be
explained by this binding model. It is also very unlikely to be solely attributed to improvement of the
physicochemical properties and/or cell permeability due to incorporation of a polar side chain.

15. PAGE 15
Characterization of 2: Binding Model Cont’d
➢ Consistent with cyclopropyl amide 7n (Figure 4), the key H-
bond interactions of the pyrimidinyl NH, thiazole N, and the
anilide NH are preserved.
➢ The critical requirement of the H-bond interactions of the
pyrimidinyl and anilide NHs for Lck activity was proved by the
lost of potency of 27, 28.
hLck (IC50 ) = 35 nM
N
S
H
N
OO
HN
Cl
7n
N
S
H
N
O
N
H
ClN
N
12m
hLck (IC50 ) = 1 nM
T-cell (IC50 ) = 80 nM
N
S
H
N
O
N
H
ClN
N
N
2
hLck (IC50 ) = 0.4 nM
T-cell (IC50 ) = 3 nM
NHO
Log P: 4.64
Log P: 5.52
Log P: 3.29
Figure 3. Enzyme activity of 27 and 28 (BMCL, 2004)
Chen, P et al, J. Med. Chem. 2006, 49, 6819-6832;
P. Chen et al. Bioorg. Med. Chem. Lett. 2004, 14, 6061–6066

16. PAGE 16
Characterization of 2 and 12m: Selectivity Against in-house Kinases
Chen, P et al, J. Med. Chem. 2006, 49, 6819-6832;
Chen, P et al. Bioorg. Med. Chem. Lett. 2004, 14, 6061–6066
➢ Compounds 12m and 2 were potent inhibitors of all Src family kinases and Bcr-Abl kinase.
➢ A high degree of selectivity (>200 fold) was observed against other tyrosine and serine/threonine
kinases.
➢ 2 was a highly potent ATP competitive inhibitor of Bcr-Abl (Ki = 30 pM).
➢ The lack of selectivity over other Src family kinases is due to the highly conserved nature of the
kinase domain among its members. In addition, the structural similarities of Lck and activated Abl
kinase may explain the strong inhibition of the Bcr-Abl kinase by these analogs (Tokarski, J. S. et
al, Cancer Res. 2006, 66, 5790-97).
2 is a sub-nanomolar inhibitor of
Pan-Src and Bcr-Abl kinases

17. PAGE 17
➢ A potent inhibitor of Src (Ki = 96 pM) and Bcr-Abl kinases (IC50 < 1.0 nM) with
antiproliferative activity versus both the PC3 human prostate tumor and the K562 human blast-
phase CML tumor cell lines.
➢ This spectrum of in vitro activity in both a hematological and a solid tumor cell line confirmed
the potential of the chemotype for oncology indications.
➢ The collection of promising data motivated investigators to characterize the compounds in an
expanded panel of cellular assays including K562, PC3, MDA-MB-231 human breast tumor and
WiDr human colon tumor cell lines.
➢ Both pyridine-based and pyrimidine based analogues demonstrated nanomolar to sub-
nanomolar inhibitory activity versus Src and Bcr-Abl. They could not be differentiated in
biochemical assays. Thus, investigators focused on activity in tumor cell proliferation assays and
mouse oral exposure screening to select compounds for in vivo evaluation in human tumor
xenograft efficacy models.
Identification of BMS-354825 (Compound 2) as a Dual Src/Abl
Kinase Inhibitor with Potent Anti-tumor Activity in Clinical Assays
Frame, M. C. Biochim. Biophys. Acta 2002, 1602, 114-130
Lombardo, L. J. et al, J. Med. Chem. 2004, 47, 6658-6661
N
S
H
N
O
N
H
ClN
N
N
2
hLck (IC50 ) = 0.4 nM
T-cell (IC50 ) = 3 nM
NHO

18. PAGE 18
SAR of Analogs Related to Compound 2 in Anti-proliferative
Activities and 4 hr Plasma Exposures
Lombardo, L.J. et al, J. Med. Chem. 2004, 47, 6658-6661 http://www.acsmedchem.org/lombardobio.html
Table 7. AntiproliferativeActivities and 4 h Plasma Exposures

19. PAGE 19
Ribbon Diagram of 2 With Abl Kinase Complex
Louis J. Lombardo et al, J. Med. Chem. 2004, 47, 6658-6661
Shah, N. P et al Science 2004, 305, 399-401
Figure1. Ribbondiagram of the Abl kinase complex
with compound 2.
➢ The activation loopofAbl , magenta, is placed in an active
conformationwhen complexedwith 2.
➢ Thees specific interactions of 2 withAbl are responsible
for the compound’s favorable activity versus mutant kinase
forms.
Key features ofthe enzyme-inhibitorcomplex:
➢ Three hydrogen bonds between compound 2 and the protein.
1) between the 2-amino hydrogen of 2 and the carbonyl oxygen
of Met318;
2) between the 3-nitrogenof the thiazole ringof 2 and the amide
nitrogenof Met318.
3) between the hydroxyl oxygen of Thr315 and the amide
nitrogenof 2.
The Abl P-loop (orange)was partiallydisordered, interactions
between thispart of the protein and 2 were less critical forbinding.

20. PAGE 20
Compound 2 Modeled into the Src Kinase ATP Binding Site
➢ All hydrogen bonds observedbetweenAbl kinase
and 2 were also observedin the Src kinase model.
➢ Additionally, a potential hydrogen bond between the
amide carbonyl of 2 and Lys295 was identified.
Louis J. Lombardo et al, J. Med. Chem. 2004, 47, 6658-6661
Figure2. Compound 2 manually docked into the Src
kinase ATP binding site. The complexis E-minimized.
In Silico depiction of 2 as a strong ATP competitive inhibitor of Src kinases

21. PAGE 21
Rat Pharmacokinetic Study of Compound 2
PK Summary:
➢ A high volume of distribution (Vss) with
systemic clearance (Cl) approximately 40% of
hepatic blood flow.
➢ A favorable half-life (t1/2) and mean residence
time (MRT).
➢ Oral bioavailability (Fpo) was 27%.
Table 3. Pharmacokinetic Properties of Compound2 in Sprague-
Dawley Rats
In conjunction with the mouse 4 hr oral exposure data, the PK profile of
compound 2 was evaluated as appropriate for continued advancement into
in vivo efficacy studies.
Louis J. Lombardo et al, J. Med. Chem. 2004, 47, 6658-6661

22. PAGE 22
In Vivo Antitumor Activity
➢ Compound 2 showed partial tumor
regressions after one treatment cycle, and
complete disappearance of the tumor mass
by the end of drug treatment.
➢ No toxicity (animal deaths, lack of weight
gain) was observed in either cohort of
animals.
Figure3. In vivo anti-tumor activity of 2 vs.
K562 xenografts innude mice (drug formulatedas
a solutionincitric acidbuffer at pH 4.6.
➢ Compound 2 possessed potent in vivo activity
➢ Compound 2 showed high safety margin in this
animal model of CML
Results:
Conclusion:
Louis J. Lombardo et al, J. Med. Chem. 2004, 47, 6658-6661

23. PAGE 23
Effect of BMS-354825 in a Mouse Model
Fig.3. Effect of BMS-354825 in a mouse model of imatinib-resistant BCR-ABL–dependent
hematopoietic disease.
(A)In vivo assay of growth inhibition of imatinib-resistant mutant BCR-ABL–expressing Ba/F3
cells. SCID mice were treated with a 50:50 mixture of propylene glycol and water (Vehicle)or
BMS-354825, beginning 3 days after infusion of the Ba/F3 cells. Images were obtained after
luciferin injection on day 13. Luciferase activity was primarily detected in the spleen.
(B)Kaplan-Meier survival analysis of BMS-354825–treated SCID mice harboring BCR-ABL-
WT,M351T, and T315I isoforms. The lone mouse with the M351T isoform that did not
survive appeared healthy on the previous day, and there was no evidence of disease at the time
of death. These experiments were repeated twice with similar results.
John S. Tokarski, et al, Cancer Res 2006; 66: (11). June 1, 2006, 5790

24. PAGE 24
Synthesis of Thiazoles Derivatives as Dual Src/Abl Kinase
Synthesis of Carboxamide, Carbamate, and Urea Analogs (5 and 7-9)

25. PAGE 25
Synthesis, cont’d
Synthesis of Heteroaryl Amines (12)

26. PAGE 26
Synthesis, cont’d
Synthesis of Compound 2

27. PAGE 27
Summary of Scientific R&D Effort
1. A novel series of substituted thiazole-5-carboxamides with
potent Src and Bcr-Abl kinase inhibitory activity was identified.
2. Analogues demonstrated broad spectrum antiproliferative
activity against hematological and solid tumor cell lines
originating in breast, prostate, and colon tissue.
3. Compound 2, a picomolar inhibitor of Src and Bcr-Abl kinase,
was orally active in a K562 xenograft model of CML,
demonstrating tumor regressions at multiple dose levels. On the
basis of its favorable in vivo efficacy and PK profile, compound
2 (BMS-354825) was advanced into clinical trials in December,
2005.
4. Compound 2 (BMS-354825) overrides Imatinib Resistance in
clinical trials. Compound 2 ( BMS-354825) is an ABL kinase
inhibitor with 2-log increased potency relative to imatinib.
Shah N et al, Science, Vol. 305 (16), 2004, 399.

28. PAGE 28
Out of the Lab: FDA Approval History for Sprycel
http://www.drugs.com/history/sprycel.html

29. PAGE 29
To the Market: Sprycel Worldwide Sales 2009-11
http://www.evaluatepharma.com/default.aspx
June 28, 2006: FDA Approval
2010: $576,000,000
2011: $803,000.000
2012: Expect > $1.1 Billion

30. PAGE 30
Publication History before Advancing Compound 2 to FDA
Chen, P et al, Discovery and Initial SAR of Imidazoquinoxalines as
Inhibitors of the Src-Family Kinase p56Lck, Bioorg. Med. Chem. Lett., 12
(2002) 1361–1364
Wityak,J et al, Discovery and initial SAR of 2-amino-5-
carboxamidothiazoles as inhibitors of the Src-family kinsae p56lck.
Bioorg. Med. Chem. Lett. 2003, 13, 4007-10.
Snow, R. J. , Discovery of 2-Phenylamino-imidazo[4,5-h]isoquinolin-9-
ones: A New Class of Inhibitors of Lck Kinase, J. Med. Chem. 2002, 45,
3394-3405
Lombardo, L. J. Discovery of N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-
hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-
carboxamide (BMS-354825), a dual Src/Ablkinase inhibitor with potent
anti-tumor activity in preclinical assays. J. Med. Chem. 2004, 47, 6658-61.
Das, J.; Ping Chen et al, 2-Aminothiazole as a Novel Kinase Inhibitor
Template. Structure-Activity Relationship Studies toward the Discovery of
N-(2-Chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl)]-2-
methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (Dasatinib,
BMS-354825) as a Potent pan-Src Kinase Inhibitor, J. Med. Chem. 2006, 49,
6819-6832

31. PAGE 31
Thanks for Your Attention
Questions:

32. PAGE 32
Backup Slides

33. PAGE 33
Backup slides: Target Validation
Targeted therapies represent the state-of-the-art in preclinical and clinical oncology research.
The use of imatinib (Gleevec) in the treatment of chronic myelogenous leukemia (CML) validated the concept that
therapeutic agents targeting cancer-specific pathways can offer significant improvements over traditional chemotherapeutic
agents.
CML is a myeloproliferative disorder that is characterized by hyperproliferation of stem cells, followed by their subsequent
differentiation into peripheral white blood cells. The presence of the Philadelphia chromosome, arising from the
translocation of the Abl kinase domain on chromosome 9 with a specific breakpoint cluster region (bcr) on chromosome 22,
is characteristic of CML. The gene product of this translocation is a constitutively activated tyrosine kinase known as Bcr-
Abl, which drives the proliferation of stem cells in the bone marrow and causes the resulting pathology of the disease. By
targeting the tyrosine kinase activity of Bcr-Abl, imatinib normalizes peripheral white blood cell counts and substantially
reduces the Philadelphia chromosome positive clone of stem cells in bone marrow, effectively offering hematological and
cytogenetic responses in the clinic.
The c-Src proto-oncogene plays a major role in the development, growth, progression, and metastasis of a wide variety of
human cancers. Src activation, in the form of elevated kinase activity and/or protein expression levels, has been
demonstrated in several major cancer types, including colon, breast, pancreatic, lung, and brain carcinomas.
Src kinase modulates signal transduction through multiple oncogenic pathways, including EGFR, Her2/neu, PDGFR,
FGFR, and VEGFR. Thus, it is anticipated that blocking signaling through the inhibition of the kinase activity of Src will
be an effective means of modulating aberrant pathways that drive oncologic transformation of cells.
Frame, M. C. Biochim. Biophys. Acta 2002, 1602, 114-130
Lombardo, L.J. et al, J. Med. Chem. 2004, 47, 6658-6661

34. PAGE 34
Backup Slide-1:
Binding Study of Compound 2 (BMS-354825)
3434
John S. Tokarski, et al, Cancer Res 2006; 66: (11). June 1, 2006, 5790
The Structure of Dasatinib (BMS-354825) Bound to Activated ABL Kinase Domain Elucidates Its
Inhibitory Activity against Imatinib-Resistant ABL Mutants

35. PAGE 35
Backup Slide-2: Structure of Dasatinib Complex
3535
A: overview of the three-dimensional structure ofABL kinase with dasatinib. Stick, dasatinib; green, carbonatoms.
Blue, NH2-terminal lobe ofABL kinase; orange, P-loop;magenta, helixa-C; red, hinge region; pink, COOH-terminal lobe;green,
catalytic loop; yellow, activation loop.
B: cut-away detailedview of dasatinib and nearby residues intheATP-binding site. Greenand blue, inhibitor molecules foundin the
two asymmetric units; gray, one proteinstructure withsurface of residues displayed. Dashed lines, hydrogen bonds.

36. PAGE 36
Backup Slide-3: Comparison of Dasatinib Complex with an
Activated Kinase
A, structure of ABL kinase (green) overlayed with LCK kinase (gray), (PDBID3LCK). Residues
important for the catalytic machinery of a typical kinase.
B, electron density of phosphorylated Y393 and nearby residues and waters.

37. PAGE 37
Backup Slide-4: A comparison of Dasatinib complex with Imatinib
Complex
3737
Figure 4. A comparison of dasatinib complex with imatinib complex.
A ribbon representationof theABL-dasatinib complex(proteinand dasatinib carbons, green) overlayed with the corresponding
complexofABL-imatinib (proteinand imatinib carbons, purple). The activation loops are labeled. Note the diverging direction
of the activation loopin the two structures. Phe382of the DFG motif (activation loop) ina dot surface representationfor each
complexto show thatimatinib would not be able to bind to the active conformationofABL because of a clash with Phe382 (as
well as other activation loopresidues) as foundin the dasatinib-bound ABL conformation. Dasatinib, on the other hand, would
be able to bind to the imatinib-bound activation loopconformation.

38. PAGE 38
Backup Slide-5: ABL-DasatinibComplex Structure Mapped into the
Imatinib-resistant Mutation Sites
3838
Figure 5. The positionof the imatinib-resistant
mutation sites are mapped onto the ABL-dasatinib
complexstructure. Orange spheres, C-a atoms.

39. PAGE 39
Backup Slide-6:
Overriding Imatinib Resistence with Compound 2 (BMS-354825)
3939
Neil P. Shah, Chris Tran, FrancisY. Lee, Ping Chen, DerekNorris, Charles L. Sawyers, Science, Vol. 305 (16), 2004, 399.
➢ Resistance to the Abl kinase inhibitor imatinib (Gleevac) in CML occurs through selection for
tumor cells harboring BCR-Abl kinase domain point mutations that interfere with drug
binding.
➢ Crystallographyc studies predict that most imatinib-resistant mutations should remain
sensitive to inhibitors that bind ABL with less stringent conformational requirements.
➢ Compound 2 ( BMS-354825) is an ABL kinase inhibitor with 2-log increased potency relative
to imatinib.