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1)Department of Science and Drug Technology, University of Torino, via Pietro Giuria 9, 10125 Torino (Italy). 2) Department of Oncology, University of Torino, via Michelangelo 27/B, 10125 Torino (Italy); 3) ProQinase GmbH, Breisacher Str. 117 D-79106, Freiburg (Germany);4) Prestwick Chemical, Bd Gonthier d’ Andernach Parc d´Innovation 67400 Illkirch (France); 5) Wiezmann Institute of Science, 234 Herzl St. Rehovot (Israel); 6) SARomics Biostructures, Lund (Sweden).
Marco L. Lolli,*1 Antonella Federico,1 Alex Ducime,1 Agnese Pippione,1 Stefano Sainas,1 Alessandro Barge,1 Katia Martina,1 Donatella Boschi,1 ���Elisa Lupino,2 Marco Piccinini,2 Michael Kubbutat,3 Jean Marie Contreras,4 Christophe Morice,4 Joel Sussman,5 Yoav Peleg,5 Bjorn Walse6 and ���
Salam Al-Kadaraghi.6
Towards a Bioisosteric Alkahest: ���application to the bioisosteric modulation of IMD-0354
O
HO
Lead structure
N
HO
Acidic group
• The Bio(iso)steric replacement is a powerful tool for the Medicinal chemist.1 It could be said that while chemistry rules the isosteric similarity between groups, only the biological target will be able to answer positively to the bioisosteric hypothesis between two groups.
• A subset of bioisosteric replacement is referred as scaffold hopping,2 where the core structure of a small molecule is replaced to move into uncharted chemical space.
!
N
HOAcidity ���
(pKa 3-6 units range)
Scaffold hopping (additional target binding opportunities)
Heteronucleus ���(influencing both pKa and logP)
(*) [email protected] www.medsynth.unito.it
• In this study, a biososteric approach was applied to the structure of IMD-0354. This potent antiinflammatory agent is claimed to selectively inhibit IKKbeta,3 the IKK sub-unity involved into the NF-kB activation during the canonical pathway.
• According to a scaffold hopping strategy,2 the bioisosteric replacement of the acidic phenolic substructure in IMD-0354 with substituted hydroxylated heterocycles afforded compounds owing different/additional binding opportunities.
• In the following, the positive results of the bioisosteric modulation as well as the characterization of the mechanism of action of IMD-0354 are presented.
0
20
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80
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120
residu
al ac+vity
(% of con
trol)
WT-‐hIKKβ
PS-‐1145 10μM
IMD-‐0354 10μM
IMD-‐0354 100μM
0
20
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80
100
120
residu
al ac+vity
(% of con
trol)
hIKKβ:11-669_S177E_S181E
PS-‐1145 10μM
IMD-‐0354 10μM
IMD-‐0354 100μM
IC50 (µM) 0.218
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residu
al ac+vity
(% of con
trol)
Ac+vity of IKK complex
10μM 25μM Stauro 1μM
PS-‐1145 10μM
50μM 100μM
IMD-‐0354
IC50(µM) 0.065
IKKbeta
Characterization of the mechanism of action of IMD-0354 and TKT0001
IMD-0354 potently inhibits the TNFα dependent activation of the canonical NF-κB signaling pathway. At the same time, against what claimed in literature,2 IMD-0354 does not show inhibitory activity on isolated WT or constitutively active hIKKβ. It is able to show only modest inhibitory activity against IKK complex purified from TNFαstimulated Jurkat cells.
OH
Cl
NH
OF
F F
F FF
• The word “alkahest’’ came directly from the alchemist’s word and reflects the search of the universality in properties. In order to develop a bioisosteric alkahest instrument able to answer positively when applied to the mimic of acidic moieties, we focused our attenction on more then 11 different acidic hydroxylated penta-atomic heterocyclic systems.
IMD-0354 0.218μM
OH
Cl
NH
OF
F F
F FF
IMD-0354
TKT0001 is able to mimic the IMD-0354 mode of action acting in the same way althrough with higher potency. To the opposite, when the two compouns were tested against a large kinase panel, TKT0001 was found to reduce the pan-activity profile of IMD-0354.
Kinase IMD-0354 TKT-0001
AMPK-alpha1 aa1-550 AXL 5,76E-05
B-RAF wt CAMKK1 1,61E-05 6,00E-05
CDK1/CycB1 6,24E-05 CHK2 1,17E-05 2,99E-05
CK1-alpha1 1,73E-05 CK2-alpha1 6,96E-05
CLK1 5,61E-05 7,81E-05 COT 2,06E-05 CSK 4,05E-05
DAPK1 DYRK1A 2,66E-05 EGF-R wt 3,87E-05 EPHA6 1,85E-05 4,31E-05 ERK2 3,18E-05
FGF-R1 wt 2,74E-05 FLT3 wt 3,51E-05
GSK3-beta 2,38E-05 HIPK1 6,59E-05
IKK-alpha 3,43E-05 IKK-beta 2,65E-05
IKK-epsilon 2,73E-05 INS-R 1,86E-05
IRAK4 (untagged) JAK1 4,82E-05
MAP3K11 MAP4K2 1,63E-05 4,53E-05 MEK1 wt
MELK 2,74E-05 MET wt 1,44E-05 MST1 3,11E-05 mTOR 3,52E-05 NEK6 2,63E-05 NIK 5,55E-05
p38-alpha 3,15E-05 PAK1 7,76E-06 1,42E-05
PCTAIRE1/CycY 3,70E-05 PDGFR-alpha wt
PDK1 1,63E-05 9,86E-05 PIM1 2,43E-05 4,78E-05
PKC-alpha 4,60E-05 PLK1 2,63E-05
SRC (GST-HIS-tag) 3,90E-05 SRPK2 SYK 3,57E-05
TAOK2 4,25E-05 TLK1 9,00E-05
1) Meanwell NA. Synopsis of some recent tactical application of bioisosteres in drug design. J Med Chem. 2011, 54(8), 2529-91.
2) Brown, N. Bioisosteres and Scaffold Hopping in Medicinal Chemistry. ���Mol. Inf. 2014, 33, 458-462.
3) Akane Tanaka, Masayo Konno, Susumu Muto, Naotomo Kambe, Eiichi Morii, Tatsutoshi Nakahata, Akiko Itai, and Hiroshi Matsuda A novel NF-kB inhibitor, IMD-0354, suppresses neoplastic proliferation of human mast cells with constitutively activated c-kit receptors, Blood 2005, 105(6), 2324.
Bibliography
Conclusions
IMD-0354 potently inhibits the TNFα dependent activation of the canonical NF-κB signaling pathway in intact cells, but neither isolated IKK nor the trimeric IKK complex appear to be a high affinity target for IMD-0354. Also TKT0001 seems to act in the same way althrough with higher potency. TKT0001 is also more selective inside a large kinases panel. More experiments are in progress to fully under stand the real mechanism of action, behind the antiinflammatory activity of both IMD-0354 and TKT0001.
TAKTIC is a consortium focused on targeting kinases funded inside 7FP by more then 1.2M Euro. It include excellence in both Academia and SME worlds.
!
TKT0001
OH
NH
OF
F F
F FF
NS N
0.065μM
\\
TKT0015 TKT00161.3 µM25.9 µM
OH
NH
OF
F F
F FF
NN
OH
NH
OF
F F
F FF
NN
TKT0002 TKT0004>100 µM>100 µM
OH
NH
O
F FF
NS N
OH
NH
O
NS N
>100 µMTKT0006
O
NH
OF
F F
F FF
NS N
IC50 profiling of IMD-0354 and TKT0001 using 48 protein kinases
TKT0222TKT0018>100 >100
OH
NH
OF
F F
F FF
NN N
OH
NH
OF
F F
F FF
NN N
TKT0011
TKT0012
TKT0008
6.93 µM
1.75 µM
OH
NH
O
F FF
NO N
OH
NH
OF
F F
F FF
NO N
NH2
NH
OF
F F
F FF
NO N
>100
TKT324TKT325>100>100
OH
O
O
NS N
OH
OH
O
NS N
TKT0007>100
OH
NH
F
F F
F FF
NS N
