Discovery of Novel Spiroindoline Derivatives as Selective Tankyrase Inhibitors

Abstract

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.

Stereoselective synthesis and applications of spirocyclic oxindoles

“…Applications. In the last decade spiropiperidinyl oxindoles have been synthesised for medicinal chemistry applications against cancer, 347 CNS disorders, 348 renal failure, 349 treatment of Dengue virus infection 350 as well as other applications. 351 Surugatoxin related to neosurugatoxin is also a potent human toxin (Fig.…”

Adp-Ribosylation as Post-Translational Modification of Proteins: Use of Inhibitors in Cancer Control

“…In the first attempts to develop ART inhibitors, few chemical structures were shown to target PARPs and tankyrases: XAV939 is a promiscuous inhibitor of PARP1 and tankyrases, while PJ34 and UPF1069 are broad PARP/tankyrase inhibitors. In recent years, inhibitors were developed specifically for tankyrases: some of them bind to the nicotinamide subsite (NS) (such as XAV939, RK-582, LZZ-02, AZ1366), or to the adenosine subsite (AS) (IWR-1, OM-1700, OD366, G007-LK and K-756) [101][102][103][104][105][106][107][108][109][110]. Dual binders (DB), recognizing both nicotinamide and adenosine subsites, have been found among PARP1 inhibitors (olaparib): for TNKS, several inhibitors showed potential therapeutic use (CMP4, WIKI4, TNKS656) [31].…”

Cell‐free in vitro reduction of carboxylates to aldehydes: With crude enzyme preparations to a key pharmaceutical building block

“…[ 39–41 ] Spirocyclic indoles are also accessible via the acid‐catalyzed Fischer reaction with substituted aryl hydrazines. [ 42 ] Applying appropriate work‐up conditions further enables access to corresponding indolinones [ 43 ] and indolines. [ 43–47 ] Robinson‐type annulation with methylvinylketone delivers 3‐azaspiroundecanones, which were used for the synthesis of several biologically active compounds.…”

“…[ 42 ] Applying appropriate work‐up conditions further enables access to corresponding indolinones [ 43 ] and indolines. [ 43–47 ] Robinson‐type annulation with methylvinylketone delivers 3‐azaspiroundecanones, which were used for the synthesis of several biologically active compounds. [ 48–50 ] Furthermore, the aldehyde moiety was addressed for classical condensation reactions with indanones, [ 51 ] Wittig reagents, [ 52 ] malonic esters, and ethyl cyanoacetate [ 53 ] (Scheme 2).…”