The canonical WNT pathway plays an
important role in cancer pathogenesis.
Inhibition of poly(ADP-ribose) polymerase catalytic activity of the
tankyrases (TNKS/TNKS2) has been reported to reduce the Wnt/β-catenin
signal by preventing poly ADP-ribosylation-dependent degradation of
AXIN, a negative regulator of Wnt/β-catenin signaling. With
the goal of investigating the effects of tankyrase and Wnt pathway
inhibition on tumor growth, we set out to find small-molecule inhibitors
of TNKS/TNKS2 with suitable drug-like properties. Starting from 1a, a high-throughput screening hit, the spiroindoline derivative 40c (RK-287107) was discovered as a potent TNKS/TNKS2 inhibitor
with >7000-fold selectivity against the PARP1 enzyme, which inhibits
WNT-responsive TCF reporter activity and proliferation of human colorectal
cancer cell line COLO-320DM. RK-287107 also demonstrated dose-dependent
tumor growth inhibition in a mouse xenograft model. These observations
suggest that RK-287107 is a promising lead compound for the development
of novel tankyrase inhibitors as anticancer agents.
An efficient and flexible synthetic route to four gem-diamine 1-N-iminosugars of uronic acid-type (D-glucuronic, D-mannuronic, L-iduronic, and L-guluronic acid), a new family of glycosidase inhibitor, from l-galactono-1,4-lactone have been developed in an enantiodivergent fashion through a sequence involving as the key steps (a) the formation of gem-diamine 1-N-iminopyranose ring by the Mitsunobu reaction of an aminal and (b) the introduction of a carboxylic acid group by the Wittig reaction of a ketone, hydroboration and oxidation, and the Sharpless oxidation. D-Glucuronic and D-mannuronic acid-type 1-N-iminosugars, (3S,4R,5R, 6R)- and (3S,4R,5R,6S)-4, 5-dihydroxy-6-trifluoroacetamido-3-piperidinecarboxylic acid, were proven to be potent inhibitors for beta-D-glucuronidase (IC(50) 6.5 x 10(-)(8)M) and to affect human heparanase (endo-beta-glucuronidase).
Tankyrases
(TNKS/TNKS2) belong to the poly(ADP-ribose) polymerase
family. Inhibition of their enzymatic activities attenuates the Wnt/β-catenin
signaling, which plays an important role in cancer pathogenesis. We
previously reported the discovery of RK-287107, a spiroindoline-based,
highly selective, potent tankyrase inhibitor. Herein we describe the
optimization process of RK-287107 leading to RK-582, which exhibits
a markedly improved robust tumor growth inhibition in a COLO-320DM
mouse xenograft model when orally administered. In addition to the
dose-dependent elevation and attenuation of the levels of biomarkers
AXIN2 and β-catenin, respectively, results of the TCF reporter
and cell proliferation studies on COLO-320DM are discussed.
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