Note
DOI: 10.1002/bkcs.12005
BULLETIN OF THE
I. Ali et al.
KOREAN CHEMICAL SOCIETY
Identification of TRD-35 as Potent and Selective DRAK2 Inhibitor
Imran Ali,†,‡,¶ Sangjun Park,†,‡,¶ Myoung Eun Jung,†,¶ Nari Lee,†,‡ Maimoona Bibi,†,‡ Chong
†,‡,
†,‡,
Hak Chae,† Kyung-Min Yang,§ Seong-Jin Kim,§, Gildon Choi,
and Kwangho Lee
*
*
*
†Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon
34114, Korea
‡Medicinal Chemistry and Pharmacology, University of Science and Technology, Daejeon 34113, Korea.
*E-mail: gchoi@krict.re.kr; kwangho@krict.re.kr
§Precision Medicine Research Center, Advanced Institutes of Convergence Technology, Seoul National
University, Suwon 16229, Korea. *E-mail: jasonsjkim@snu.ac.kr
¶These authors contributed equally to this work.
Received January 14, 2020, Accepted February 20, 2020
Keywords: DRAK2, DRAK1, DAPK1, DAPK3, Kinase, Inhibitor, 3-Aminopyrazoylpyrimidine
DAP kinase-related apoptosis-inducing protein kinase
2 (DRAK2) is a member of the death-associated protein
kinase (DAPK) family1 and originally identified as a
proapoptotic protein with the ability to induce apoptosis
when overexpressed in various cell types.2 However, the
apoptosis-inducing ability of DRAK2 seems to be contro-
versial and influenced by cellular factors within a specific
cell types.3,4 Recently, it has been suggested that DRAK2
is closely involved in tumorigenesis; DRAK2 expression
was found to be highly elevated in multiple tumor types
such as basal-like and HER2-enriched breast cancers. In
addition, knockdown of the gene resulted in significant
tumor growth inhibition in a mouse xenograft animal
model. Yang et al. also reported the experimental evidence
suggesting that DRAK2 acts as a negative regulator of
TGF-β mediated signal transduction pathway.5 Aberrant
expression of DRAK2 accelerates the tumorigenesis pro-
cess by constraining the tumor suppressor activity of
TGF-β.
While growing evidence strongly indicates that DRAK2
is a promising target for drug development, only a small
number of DRAK2 inhibitors have been reported in the lit-
erature to date (Figure 1). Compounds with benzofuran-3
(2H)-one core were found to have a strong binding affinity
for DRAK2 from in vitro kinase assays and displayed a sig-
nificant cellular activity that can protect islet β-cells from
apoptosis.6 A series of thieno[2,3-b]pyridine derivatives
have been shown to have strong DRAK2 binding activity
while lacking DRAK1 selectivity.7 Recently, Jung et al.
reported indirubin-30-oximes as potent DRAK2 inhibitors.8
To identify selective DRAK2 inhibitor motif, DRAK2
X-ray co-crystal structure (PDB databank 3LM0) with
DRAK2 ATP-binding site inhibitor (Vertex-3) was re-vis-
ited. Vertex-3 is a pyrimidine C5-methylated analog of
UC-3.9 When UC-3 was assessed to ATP-binding site of
359 diverse kinases at 10 micromolar concentration, it
bound to 337 kinases including CDK2, CDK5, JNK3, and
others. In particular, all the DAPK family kinase
(DAPK1,2,3 and DRAK 1,2) activities were significantly
inhibited by UC-3. Therefore, UC-3 is a potent DRAK2
inhibitor along with promiscuous multi-kinase binding. In
this note, we wish to report part of our efforts to identify
potent and selective DRAK2 inhibitor from promiscuous
kinase inhibitor UC-3. We believe the nitrile of the UC-3
has hydrogen-bonding interaction to DRAK2 Lys62 and
plays a key role for its kinase promiscuous activities. To
secure structural novelty from UC-3, the nitrile of the UC-
3 was attempted to displace with various functional groups
(Figure 2). Once novel non-nitrile motif is identified, the
pyrimidine C5 position would be explored for DRAK2
potency and selectivity. Finally, optimal alkyl substitution
of C5-pyrazol could be re-visited.
After extensive the nitrile displacement survey, met-
hylsulfonylmethyl was proven to be non-inferior to the
nitrile in terms of DRAK2 activity (survey data not shown).
To this end, TRD-35 was identified as a non-nitrile con-
taining lead for DRAK2 inhibitor.
Figure 2. Vertex-3, UC-3 and DRAK2 medicinal chemistry strat-
egy (to be re-sized).
Figure 1. Reported DRAK2 inhibitors (to be re-sized).
Bull. Korean Chem. Soc. 2020
© 2020 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Wiley Online Library
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