Biomedical Engineering Reference
In-Depth Information
N
N
N
N
N
N
N
N
O
O
N
N
R1
6
3'
A: R1 = H
B: R1 = Me
N
N
C: Gleevec
Comp./activity IC50 (μM)
v-Abl-K
PKCα
PKCβ
A
B
C
0.4
1.2
23
0.4
72
>500
(B)
0.038
>100
>100
Thr 315
Met 318
Glu 286
Asp 381
Ile 360
(C)
FIGURE 23.7 (conitnued)
(B) Chemical structure of Gleevec and associated kinase inhibitors. Table shows
the effect of SAR variations on the activity toward BCR-ABL and protein kinase C, α, and β isoforms.
(C) Crystal structure of the catalytic domain of ABL tyrosine kinase complexed with Gleevec. Hydrogen bonds
with interacting amino acids are indicated. (Computer model courtesy of Dr. S. Vadlamudi, Topotarget, U.K.)
The presence of the BCR-ABL protein exclusively in CML cells (cancer specii city) combined
with the cellular dependence on this sole protein for survival of transformed cells (also referred to as
oncogene addiction) represents an unique situation where targeted cancer therapy is relatively easily
achieved. Thus, the development of Gleevec is one of the best examples of a modern targeted anti-
cancer therapeutics, and its design builds on a clear rational for intervention (in this case oncogene
addiction), combined with detailed knowledge of the three-dimensional structure of the primary
molecular target (the BCR-ABL onco-protein). The successful launching of Gleevec has provided a
great deal of inspiration and effort into the further development of small molecule kinase inhibitors
as anticancer drugs. The i nding that Gleevec also inhibits c-KIT has promoted its recent use in the
treatment of colorectal cancers.
The molecular starting point for the medicinal chemistry leading to the development of Gleevec
was a phenylaminopyrimidine derivative (the blue core of compound A/B as contained in the box
