G007-LK / Roche, University of Oslo, ODIN Therap - LARVOL DELTA

From sterility to selectivity: a C. elegans synthetic lethality screen reveals non-conserved vulnerabilities in ATRX-deficient glioma (EANO 2025) - "Corresponding small-molecule inhibitors—TAK-981 (SUMO pathway), UNC-0642 (H3K9 methylation), and G007-LK (tankyrase inhibition)—were evaluated in ATRX-deficient HeLa-LT and SF188 cell lines. Cell viability was measured under single-agent and combination treatments with DNA-damaging agents (doxorubicin, bleomycin). RNAi of top hits, including gei-17 and set-25, induced significant fertility defects in xnp-1 mutants...Although the candidate compounds identified through C. elegans synthetic sterility screens did not produce selective cytotoxicity in ATRX-deficient human cancer cells, this outcome provides valuable insight into the translational landscape of cross-species screening. The fertility-based phenotype in xnp-1 mutants likely captures gene interactions relevant to germline development and stress responses, which may not be conserved in cancer biology. By reporting these results, we aim to contribute to a more informed and efficient use of model organisms in..."

Synthetic lethality • Brain Cancer • Glioma • Oncology • Solid Tumor • ATRX

3D layered co-culture model enhances Trastuzumab Deruxtecan sensitivity and reveals the combined effect with G007-LK in HER2-positive non-small cell lung cancer. (PubMed, Biochem Biophys Res Commun) - "This combined effect was also observed in H2170, an HER2-amplified lung cancer cell line. These results suggest that the proposed 3D co-culture system may help in evaluating the efficacy of T-DXd and may recapitulate the tumor microenvironment."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HER-2

APC/PIK3CA mutations and β-catenin status predict tankyrase inhibitor sensitivity of patient-derived colorectal cancer cells. (PubMed, Br J Cancer) - "APC/PIK3CA mutations and β-catenin predict the sensitivity of APC-mutated CRC PDCs to tankyrase inhibitors. These observations may help inform the strategy of patient selection in future clinical trials of tankyrase inhibitors."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • APC • BRAF • CTNNB1 • KRAS • PIK3CA • PRKDC

Design, synthesis, and biological activity evaluation of new tankyrase-2 directed inhibitors. (PubMed, Chem Biol Drug Des) - "Among them, compound 14e showed better inhibition potency against TNKS2 in comparison with G007-LK, one of the most potent preclinical stage TNKS inhibitor. Molecular docking results showed that 14e occupied both the adenosine and nicotinamide pockets and formed a hydrogen bond with Met1054 of TNKS2. This study provides a lead for the design and discovery of potent and selective TNKS2 inhibitors."

Journal • TNKS2

Differential requirement of Hippo cascade during CTNNB1 or AXIN1 mutation driven hepatocarcinogenesis. (PubMed, Hepatology) - "Our studies demonstrate that YAP/TAZ are major signaling molecules downstream of LOF AXIN1 mutant HCCs, and targeting YAP/TAZ as an effective treatment against AXIN1 mutant human HCCs."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • AXIN1 • CTNNB1 • LATS2

Tankyrase-selective inhibitor STP1002 shows preclinical antitumour efficacy without on-target toxicity in the gastrointestinal tract. (PubMed, Eur J Cancer) - "These results demonstrate that STP1002, a novel, orally active tankyrase inhibitor, shows preclinical antitumour efficacy without on-target toxicity in the GI tract. Our data provide a rationale for a clinical trial on STP1002 as a potential tankyrase-targeted drug in patients with APC-mutated CRC."

Journal • Preclinical • Colorectal Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Oncology • Solid Tumor • APC • PARP1

Tankyrase inhibitors hinder Trypanosoma cruzi infection by altering host-cell signalling pathways. (PubMed, Parasitology) - "We showed that five TNKSi (FLALL9, MN64, XAV939, G007LK and OULL9) diminished T. cruzi infection of Vero cells. Further signals should be monitored in this model and in vivo. As a TNKSi has entered cancer clinical trials with promising results, our findings encourage further studies aiming at drug repurposing strategies."

Journal • Infectious Disease • Oncology • PARP1 • TNFA

Identification of response signatures for tankyrase inhibitor treatment in tumor cell lines. (PubMed, iScience) - "The TNKS1/2-specific inhibitor G007-LK was used to screen 537 human tumor cell lines and a panel of particularly TNKSi-sensitive tumor cell lines was identified...Moreover, we show that TNKSi induces accumulation of TNKS1/2-containing β-catenin degradasomes functioning as core complexes interacting with YAP and angiomotin proteins during attenuation of YAP signaling. These findings provide a contextual and mechanistic framework for using TNKSi in anticancer treatment that warrants further comprehensive preclinical and clinical evaluations."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • CTNNB1 • TNKS2 • YAP1

Targeting of canonical WNT signaling ameliorates experimental sclerodermatous chronic graft-versus-host disease. (PubMed, Blood) - "Treatment with highly selective tankryase inhibitor G007-LK, CK1α agonist pyrvinium or LRP6 inhibitor salinomycin, abrogated the activation of WNT signaling and protected against experimental cGvHD, without significant impact on graft-versus-leukemia effect (GvL). Inhibition of canonical WNT signaling reduced the release of extracellular matrix from fibroblasts and reduced leukocyte influx, suggesting that WNT signaling stimulates fibrotic tissue remodeling by direct effects on fibroblasts and by indirect, inflammation-dependent effects in sclGvHD. Our findings may have direct translational potential, as pyrvinium is in clinical use and tankyrase inhibitors are in clinical trials for other implications."

Journal • Fibrosis • Graft versus Host Disease • Hematological Malignancies • Immunology • Inflammation • Leukemia • Oncology • Scleroderma • Systemic Sclerosis • Transplantation

[VIRTUAL] Tankyrase inhibitors: Evidence for therapeutic potential in immuno-oncology (ACS-Fall 2020) - "Several small molecules have been identified that inhibit tankyrase 1 and 2, and we have earlier shown efficacy of tankyrase inhibitors in WNT dependent adenoma and tumor models.Here we describe the successful discovery of the selective and highly potent tankyrase inhibitor, OM-153, our preclinical candidate, starting from the initial lead molecule G007-LK. In addition, we present a proof of concept study for selective tankyrase inhibition as an immune modulatory strategy in the oncology arena."

Immune Modulation • Inflammation • Oncology • PARP1