Identification
of the Privileged Position in the Imidazo[1,2‑a]pyridine Ring of Phosphonocarboxylates for Development
of Rab Geranylgeranyl Transferase (RGGT) Inhibitors
Version 2 2017-10-18, 15:22
Version 1 2017-10-17, 18:59
Posted on 2017-10-18 - 15:22
Members of the Rab
GTPase family are master regulators of vesicle
trafficking. When disregulated, they are associated with a number
of pathological states. The inhibition of RGGT, an enzyme responsible
for post-translational geranylgeranylation of Rab GTPases represents
one way to control the activity of these proteins. Because the number
of molecules modulating RGGT is limited, we combined molecular modeling
with biological assays to ascertain how modifications of phosphonocarboxylates,
the first reported RGGT inhibitors, rationally improve understanding
of their structure–activity relationship. We have identified
the privileged position in the core scaffold of the imidazo[1,2-a]pyridine ring, which can be modified without compromising
compounds’ potency. Thus modified compounds are micromolar
inhibitors of Rab11A prenylation, simultaneously being inactive against
Rap1A/Rap1B modification, with the ability to inhibit proliferation
of the HeLa cancer cell line. These findings were rationalized by
molecular docking, which recognized interaction of phosphonic and
carboxylic groups as decisive in phosphonocarboxylate localization
in the RGGT binding site.
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Kaźmierczak, Aleksandra; Kusy, Damian; Niinivehmas, Sanna P.; Gmach, Joanna; Joachimiak, Łukasz; Pentikäinen, Olli T.; et al. (2017). Identification
of the Privileged Position in the Imidazo[1,2‑a]pyridine Ring of Phosphonocarboxylates for Development
of Rab Geranylgeranyl Transferase (RGGT) Inhibitors. ACS Publications. Collection. https://doi.org/10.1021/acs.jmedchem.7b00811
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AUTHORS (8)
AK
Aleksandra Kaźmierczak
DK
Damian Kusy
SN
Sanna P. Niinivehmas
JG
Joanna Gmach
ŁJ
Łukasz Joachimiak
OP
Olli T. Pentikäinen
EG
Edyta Gendaszewska-Darmach
KB
Katarzyna M. Błażewska
KEYWORDS
Rab Geranylgeranyl TransferaseRap 1A modificationcompoundphosphonocarboxylate localizationHeLa cancer cell lineRab GTPase familymicromolar inhibitorsRGGT binding sitepyridine Ringcarboxylic groupsRab 11A prenylationpost-translational geranylgeranylationvesicle traffickingPrivileged PositionRab GTPasesmaster regulatorscore scaffoldmolecules modulating RGGTRGGT inhibitorsInhibitors Members