DOI: 10.1002/cmdc.201600224
Communications
Discovery of a Nanomolar Multikinase Inhibitor
(KST016366): A New Benzothiazole Derivative with
Remarkable Broad-Spectrum Antiproliferative Activity
Ashraf Kareem El-Damasy,[a, b, c] Nam-Chul Cho,[a] Ghilsoo Nam,[a, b] Ae Nim Pae,[a, b] and
Herein we report the discovery of compound 6 [KST016366; 4-
((2-(3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phe-
cal cytotoxic drugs to targeted agents that modulate protein
kinases whose activities are more specifically linked with can-
cerous cells.[3]
nyl)ureido)benzo[d]thiazol-6-yl)oxy)picolinamide] as
a
new
potent multikinase inhibitor through minor structural modifica-
tion of our previously reported RAF kinase inhibitor A. In vitro
anticancer evaluation of 6 showed substantial broad-spectrum
antiproliferative activity against 60 human cancer cell lines. In
particular, it showed GI50 values of 51.4 and 19 nm against leu-
kemia K-562 and colon carcinoma KM12 cell lines, respectively.
Kinase screening of compound 6 revealed its nanomolar-level
inhibitory activity of certain oncogenic kinases implicated in
both tumorigenesis and angiogenesis. Interestingly, 6 displays
IC50 values of 0.82, 3.81, and 53 nm toward Tie2, TrkA, and ABL-
1 (wild-type and T315I mutant) kinases, respectively. Moreover,
6 is orally bioavailable with a favorable in vivo pharmacokinetic
profile. Compound 6 may serve as a promising candidate for
further development of potent anticancer chemotherapeutics.
In solid tumors, it is unusual for a single kinase aberration to
be the sole cause of disease and it is improbable that tumors
are dependent on only one dysregulated signaling pathway.[4]
In this regard, inhibition of a single kinase may not be suffi-
cient to achieve a clinical benefit, due to either the built-in re-
dundancy of signaling pathways, or the ability of tumors to ac-
quire resistance.[5,6] Therefore, multikinase Inhibitors have
emerged as a new paradigm in drug discovery to overcome
the resistance arising from selective kinase inhibitors.[7,8] Cur-
rently, a number of multitargeted kinase inhibitors are com-
mercially launched.
The absolute majority of kinase inhibitors are known as
type I inhibitors, which target the ATP-site of the kinase in its
active state (DFG-in). In contrast, type II inhibitors trap their
target kinases in the inactive (DFG-out) conformation, occupy-
ing a hydrophobic pocket adjacent to the ATP binding site.[9]
Sorafenib (Nexavarꢀ) is a multikinase type II inhibitor approved
by the Food and Drug Administration (FDA) for treatment of
advanced renal carcinoma.[10] Structural analysis of the co-crys-
tal structure of sorafenib[11] and other type II kinase inhibi-
tors[12,13] with their kinases (BRAF, c-KIT and ABL) defined the
prerequisite structural features to access type II binding confor-
mation.[14] Accordingly, sorafenib structure could be dissected
into the head pyridine moiety as hinge region binder, central
phenyl ring linker, urea as hydrogen bond donor/acceptor pair,
and a hydrophobic tail (4-chloro-3-trifluoromethylphenyl termi-
nal) that access the hydrophobic pocket created by the flip of
the DFG motif of the kinase activation loop.[15]
Cancer is still a prime leading cause of mortality worldwide, ac-
counting for 8.2 million deaths in 2012.[1] Cancer reflects a mul-
tistep process, arising from accumulation of hereditary and/or
acquired disorders in genes involved in the regulation of cell
propagation and survival. Activation or inactivation of four or
five different genes may be needed for the development of
a clinically detectable human cancer.[2] The conventional cyto-
toxic chemotherapeutics that directly interact with DNA are
one of the cornerstones for cancer treatment. However, their
severe side effects constitute a major obstacle that impedes
their efficacy. Over the past two decades, the attention of anti-
cancer drug development has shifted dramatically from classi-
Recently, we reported a series of 2-ureidoquinolines[16] and
ureidobenzothiazoles[17] derivatives as sorafenib congeners by
replacing the central phenyl linker of sorafenib with either qui-
nolone[16] or benzothiazole[17] scaffold, while conserving the
other structural features. Interestingly, such modifications led
to considerable improvement in the cellular anticancer poten-
cy as well as favorable inhibitory activity toward B-RafV600E and
C-Raf kinases.
[a] A. K. El-Damasy, Dr. N.-C. Cho, Prof. G. Nam, Prof. A. N. Pae, Prof. G. Keum
Center for Neuro-Medicine, Brain Science Institute,
Korea Institute of Science and Technology (KIST),
Hwarangro 14-gil 5, Seongbuk-gu, Seoul 136-791 (Republic of Korea)
[b] A. K. El-Damasy, Prof. G. Nam, Prof. A. N. Pae, Prof. G. Keum
Department of Biological Chemistry,
Korea University of Science and Technology (UST),
Gajungro 217, Youseong-gu, Daejeon 305-350 (Republic of Korea)
In the present study, we aimed at performing further struc-
tural modifications in terms of the hydrophobic tail, in an at-
tempt to improve the anticancer activity of the ureidobenzo-
thiazole A.[17] We thought that replacing the small lipophilic
chlorine atom of A with either (morpholin-1-yl)methyl 5 or (4-
ethylpiperazin-1-yl)methyl moiety 6 (Figure 1) may improve
the physicochemical properties of compound A and hence its
[c] A. K. El-Damasy
Department of Medicinal Chemistry,
Faculty of Pharmacy, University of Mansoura, Mansoura 35516 (Egypt)
Supporting information (detailed procedures for synthesis, cellular and
biochemical assays, and molecular docking) and the ORCID identification
number(s) for the author(s) of this article can be found under http://
ChemMedChem 2016, 11, 1 – 10
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