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- Preclinical characterization of NTX-452, a potent, selective and highly efficacious WRN inhibitor for the treatment of MSI-H tumors (Exhibition Hall) - Sep 7, 2024 - Abstract #EORTCNCIAACR2024EORTC_NCI_AACR_461;
Unless they are part of the media programme, embargoed or not consented, all abstracts will be released on 9 October 2024. All other abstracts will be released on the day of presentation.
- Undisclosed WRN inhibitor / Ideaya Biosci, GSK
On-target mutations drive resistance to WRN helicase inhibitors in microsatellite unstable colorectal cancer (Room 111 + 112) - Sep 7, 2024 - Abstract #EORTCNCIAACR2024EORTC_NCI_AACR_424;
Results were validated in cell and patient-derived xenograft models treated with multiple WRN inhibitors, and drug cross-resistance studies are ongoing. This study indicates that on-target WRN mutations are a key driver of drug resistance, provides a platform to evaluate drug cross-resistance, and can inform potential resistance mechanisms observed in WRNi clinical trials.
- Discovery of WRN inhibitors as targeted therapy in the treatment of microsatellite unstable (MSI-H) tumors (Exhibition Hall) - Sep 7, 2024 - Abstract #EORTCNCIAACR2024EORTC_NCI_AACR_127;
Unless they are part of the media programme, embargoed or not consented, all abstracts will be released on 9 October 2024. All other abstracts will be released on the day of presentation.
- | Journal, Microsatellite instability: PROTAC-mediated conditional degradation of the WRN helicase as a potential strategy for selective killing of cancer cells with microsatellite instability. (Pubmed Central) - Sep 7, 2024
We also describe a multi-colour cell-based platform for facile testing of selective toxicity in MSI versus MSS cell lines. Together, our data show that a degrader approach is a potentially powerful way of targeting WRN in MSI cancers and paves the way for the development of WRN-specific PROTAC compounds.
- | Journal: WRN Helicase: Is There More to MSI-H than Immunotherapy? (Pubmed Central) - Aug 2, 2024
They demonstrate that WRN inhibitors may be even more effective in a subset of MSI-high tumors with (TA)n repeat expansions, which represents a possible strategy in clinical development. See related article by Picco et al., p. 1457 (1).
- | HRO761 / Novartis
Journal, Synthetic lethality: Discovery of WRN inhibitor HRO761 with synthetic lethality in MSI cancers. (Pubmed Central) - May 8, 2024
P1
These findings represent preclinical pharmacological validation of WRN as a therapeutic target in MSI cancers. A clinical trial with HRO761 (NCT05838768) is ongoing to assess the safety, tolerability and preliminary anti-tumour activity in patients with MSI colorectal cancer and other MSI solid tumours.
- | Journal: Challenges for the Discovery of non-covalent WRN Helicase inhibitors. (Pubmed Central) - Apr 22, 2024
Previously published WRN Helicase inhibitors (ML216, NSC19630 or NSC617145) were characterized in an extensive set of biochemical and biophysical assays and could be ruled out as specific WRN helicase probes. More innovative screening strategies need to be developed for successful drug discovery of non-covalent WRN helicase inhibitors.
- | Journal, MSi-H Biomarker: Discovering potential WRN inhibitors from natural product database through computational methods. (Pubmed Central) - Apr 15, 2024
Subsequent molecular dynamics simulation revealed that these screened natural products possessed better binding dynamic characteristics than ATP substrate and were capable of inhibiting the dynamic process of WRN, making them potential strong ATP competitive inhibitors. In conclusion, our computational approach revealed potential WRN inhibitors from a natural product database, providing a theoretical basis for future research.
- | Undisclosed WRN inhibitor / Ideaya Biosci, GSK
Journal, IO biomarker: Novel WRN Helicase Inhibitors Selectively Target Microsatellite Unstable Cancer Cells. (Pubmed Central) - Apr 8, 2024
Efficacy was confirmed in immunotherapy-resistant organoids and patient-derived xenograft (PDX) models. The discovery of potent, selective covalent WRN inhibitors provides proof of concept for synthetic-lethal targeting of WRN in MSI cancer and tools to dissect WRN biology.
- | Journal: Targeting ATP-binding site of WRN Helicase: Identification of novel inhibitors through pocket analysis and Molecular Dynamics-Enhanced virtual screening. (Pubmed Central) - Mar 23, 2024
We also investigated the binding mode of these compounds to WRN's ATP-binding sites. These findings offer a promising strategy for discovering new WRN inhibitors and present two novel scaffolds, which might be potential for the development of MSI cancer treatment.
- INSULIN SENSITIVITY AND SECRETION BIOMARKERS IN HOMOZYGOTE VS HETEROZYGOTE FAMILY MEMBERS FOR THE PATHOGENIC WRN GENE MUTATION (WERNER SYNDROME) () - Mar 17, 2024 - Abstract #ICEEDEC2024ICE_EDEC_1011;
In-depth molecular and mechanistic studies could lead to novel "insulin sensitisers", to better treat insulin resistance in type 2 diabetes and related disorders. Figure 1: Figure 2:
- HRO761 / Novartis
Discovery of HRO761, a novel, first-in-class clinical stage WRN inhibitor with potent anti-tumor activity in microsatellite instability high cancers (Hybrid; Room 355 (Ernest N. Morial Convention Center)) - Mar 12, 2024 - Abstract #ACSSp2024ACS_Sp_12041;
Pharmacological inhibition of WRN by HRO761 recapitulates the phenotype observed by WRN genetic suppression, validating WRN as a therapeutic target in MSI high cancers. A phase 1 clinical trial with HRO761 is currently ongoing to assess the safety, tolerability, and preliminary anti-tumor activity in patients with MSI high colorectal cancer and other MSI high solid tumors.
- Discovery of a novel WRN inhibitor, ZM-3329 that efficiently inhibits MSI-H tumor growth (Section 28) - Mar 5, 2024 - Abstract #AACR2024AACR_9406;
In conclusion, a novel WRN inhibitor was developed, and robust antitumor activities were demonstrated in xenograft tumors and PDOs with different tissue types. In terms of synthetic lethality between MSI-H and WRN as well as broad anti-tumor activities across different tumor types, ZM-3329 would be developed as a tissue-agnostic therapy for MSI-H patients.
- GH1581 / Genhouse Bio
Discovery of GH1581, a potent and selective WRN inhibitor as a cancer therapy (Section 44) - Mar 5, 2024 - Abstract #AACR2024AACR_9231;
In SW48 xenograft model, it inhibited the tumor growth with 100% TGI at QD dosing of 10 mg/kg without severe adverse effect on body weight. In summary, we discovered GH1581 as a novel inhibitor of WRN with high in vitro and in vivo efficacy.
- Undisclosed WRN inhibitor / Ideaya Biosci, GSK
Novel WRN helicase inhibitors selectively target microsatellite unstable cancer cells (Ballroom 6 DE - Upper Level - Convention Center) - Mar 5, 2024 - Abstract #AACR2024AACR_8829;
Efficacy was also confirmed in patient-derived organoids and PDX models refractory to immunotherapy. The discovery of potent and selective covalent WRN inhibitors provides proof-of-concept for targeting MSI cancers and provides tools to unlock the molecular dissection of the WRN biology and MSI synthetic lethality.
- A WRN screening cascade to facilitate novel drug discovery (Section 14) - Mar 5, 2024 - Abstract #AACR2024AACR_8383;
J Invest Dermatol. 2021 Apr; 141(4S):968-975.
- Undisclosed WRN inhibitor / Ryvu Therap
Discovery of WRN inhibitors as targeted therapy in the treatment of microsatellite unstable (MSI-H) tumors (Section 26) - Mar 5, 2024 - Abstract #AACR2024AACR_8167;
The correlation between compound exposure and on-target effect was confirmed in PK/PD and efficacy studies in xenograft MSI-H cancer models. These data provide pharmacological proof-of-concept for the synthetic lethal effect of our inhibitors and support WRN inhibition as a new oncological therapy.
- PH027-1 / Suzhou Puhe Pharma
PH027-1, a potent and selective small-molecule WRN inhibitor that targets MSI-H tumors (Section 26) - Mar 5, 2024 - Abstract #AACR2024AACR_8146;
These data provide pharmacological proof-of-concept for the synthetic lethal effect of our inhibitors and support WRN inhibition as a new oncological therapy. As a highly selective and potent inhibitor on helicase activity of WRN, PH027-1 has the potential to become a novel and safe approach for treatment of MSI-H tumors.
- Germanin (suramin) / Optimum Therap
Development of HTS enzymatic assays for WRN helicase and exonuclease functions (Section 20) - Mar 5, 2024 - Abstract #AACR2024AACR_4911;
There are no published inhibitors for the WRN exonuclease, but suramin inhibited with an IC50 of approximately 100 nM. These assays allow sensitive, robust, quantitative detection of WRN ATPase and exonuclease activities using an extensively validated HTS platform; they should be valuable tools for screening and optimizing small molecules targeting specific WRN functions.
- A high-throughput phenotypic screen to identify small molecule inhibitors of Werner helicase (Section 20) - Mar 5, 2024 - Abstract #AACR2024AACR_4893;
Validation studies including the assessment of cell viability and DNA damage in a panel of MSI-H and MSS cell lines will be performed. Our study proposes a phenotypic screening strategy for identifying small molecules with the potential to target WRN and uncover additional novel mechanisms for treating MSI-H cancers.
- ISM9342A / Insilico Medicine
Discovery and preclinical characterization of ISM9342A, a novel, potent, and orally bioavailable WRN inhibitor that suppresses MSI-H tumor growth (Section 17) - Mar 5, 2024 - Abstract #AACR2024AACR_2922;
ISM9342A demonstrated good drug-like properties, including excellent in vitro ADMET profiles and good in vivo exposure, including low clearance and optimal oral bioavailability across multiple preclinical species. Collectively, these findings highlight the potential of ISM9342A as a highly potent WRN inhibitor for the treatment of MSI-H tumors
- | Journal, Microsatellite instability: Discovery of thiophen-2-ylmethylene bis-dimedone derivatives as novel WRN inhibitors for treating cancers with microsatellite instability. (Pubmed Central) - Feb 19, 2024
Furthermore, we demonstrated that the optimal compound induced DNA damage and apoptotic cell death in MSI cancer cells by inhibiting WRN. This study provides a new pharmacophore for WRN inhibitors, emphasizing their therapeutic potential for MSI cancers.
- Mechanisms and clinical study design to examine the synthetic lethality of WRN inhibitors with mismatch repair deficiency (Room 11 - Upper Level - Convention Center) - Feb 5, 2024 - Abstract #AACR2024AACR_356;
This study provides a new pharmacophore for WRN inhibitors, emphasizing their therapeutic potential for MSI cancers. There is no abstract associated with this presentation.
- ED13- New Targets and Mechanisms of Synthetic Lethality in Cancer Therapy (Room 11 - Upper Level - Convention Center) - Feb 5, 2024 - Abstract #AACR2024AACR_349;
The third talk by Zev A Wainberg will explore the efforts to develop WRN inhibitors for the treatment of mismatch repair deficient cancers. WRN inhibitors being developed by Novartis and Vividion/Roche are entering clinical trials.
- | Journal: Early-onset diabetes mellitus as a presenting feature of Werner's syndrome in an Indian family. (Pubmed Central) - Jan 30, 2024
Our report brings to attention the onset of DM during childhood or early adulthood in patients with Werner's syndrome who typically develop type 2 DM around the age of 30-40?years. Presence of consanguinity among parents, dysmorphic features, and malignancy should prompt consideration of diagnosis of Werner's syndrome.
- HRO761 / Novartis
HRO761, a first-in-class, clinical stage WRN inhibitor with potent preclinical anti-tumor activity in MSIhigh models. (LEVEL 2, EXHIBIT HALL D) - Sep 16, 2023 - Abstract #AACRNCIEORTC2023AACR_NCI_EORTC_462;
- HRO761 / Novartis
HRO761, a first-in-class clinical stage WRN inhibitor with potent anti-tumor activity in microsatellite instability high cancers. (LEVEL 2, EXHIBIT HALL D) - Sep 16, 2023 - Abstract #AACRNCIEORTC2023AACR_NCI_EORTC_455;
- HRO761 / Novartis
HRO761, a first-in-class clinical stage WRN inhibitor with potent anti-tumor activity in microsatellite instability high cancers* (LEVEL 2, BALLROOM AB) - Sep 16, 2023 - Abstract #AACRNCIEORTC2023AACR_NCI_EORTC_150;
- Tevimbra (tislelizumab) / BeiGene, HRO761 / Novartis
A phase I/Ib study of the Werner (WRN) helicase inhibitor HRO761 as single agent and in combination with irinotecan or tislelizumab in patients with microsatellite instability-high (MSIhi) or mismatch repair deficient (dMMR) advanced solid tumors () - Jul 27, 2023 - Abstract #ESMO2023ESMO_2292;
P1
Key eligibility criteria include: 1) Patients with advanced unresectable or metastatic MSIhi or dMMR solid tumors who have progressed after or are intolerant to prior standard therapy; 2) patients should have received at least one prior line of chemotherapy or targeted therapy, and prior immune checkpoint inhibitor therapy (Arm A and C). Checkpoint inhibitor therapy is permitted but not required and prior adjuvant therapy is allowed in Arm B.
- MSI cancer associated DNA (TA)n-dinucleotide repeat expansions and implications for Werner synthetic lethality (Section 37; Poster Board #2) - Mar 14, 2023 - Abstract #AACR2023AACR_5797;
Our data provide fresh insights into the inter and intra-tumoral heterogeneity of TA-dinucleotide repeat expansions in human cancers. These data contribute to understanding the role of MMR in cancer and exploiting Werner as a therapeutic target in cancer.
- A small-molecule inhibitor of WRN selectively kills MSI-H cancer cells and phenocopies WRN genetic defects (Section 17; Poster Board #18) - Mar 14, 2023 - Abstract #AACR2023AACR_3873;
In vivo evaluation demonstrated robust and MSI-selective tumor regressions. These data provide pharmacological proof-of-concept for the WRN/MSI-H synthetic lethal relationship and support WRN inhibition as a novel therapeutic approach for the treatment of MSI-H cancers.
- || Review, Journal: Clinical prospects of WRN inhibition as a treatment for MSI tumours. (Pubmed Central) - Nov 18, 2022
Furthermore, the complexities of MSI development and its relationship to cancer evolution pose challenges for clinical prospects. Here, we discuss possible paths of MSI tumour development, the viability of WRN inhibition as a strategy in different scenarios, and the necessary conditions to create a roadmap towards successful implementation of WRN inhibitors in the clinic.
- (TA)n-dinucleotide repeat expansions in MSI cancers and implications for Werner synthetic lethality (Poster Area) - Jun 28, 2022 - Abstract #EACR2022EACR_1003;
Conclusion Our data provide fresh insights into the inter and intra-tumoral heterogeneity of TA-dinucleotide repeat expansions in human cancers. These data contribute to understanding the role of WRN in cancer and exploiting Werner as a therapeutic target in cancer.
- | Journal, Mismatch repair, MSi-H Biomarker, IO biomarker, Synthetic lethality: Werner helicase is a synthetic-lethal vulnerability in Mismatch Repair-Deficient Colorectal Cancer Refractory to Targeted Therapies, Chemotherapy and Immunotherapy. (Pubmed Central) - Feb 26, 2022
Furthermore, models of resistance to clinically relevant targeted therapy, chemotherapy, and immunotherapy retain WRN dependency. These data show the potential of therapeutically targeting WRN in dMMR/MSI-H CRC patients, and support WRN as a therapeutic option for patients with dMMR/MSI-H cancers refractory to current treatment strategies.
- | chloroquine phosphate / Generic mfg.
Journal, Epigenetic controller: WRN inhibits oxidative stress-induced apoptosis of human lensepithelial cells through ATM/p53 signaling pathway and its expression is downregulated by DNA methylation. (Pubmed Central) - Sep 10, 2021
These data show the potential of therapeutically targeting WRN in dMMR/MSI-H CRC patients, and support WRN as a therapeutic option for patients with dMMR/MSI-H cancers refractory to current treatment strategies. Our study reveals that DNA methylation mediated WRN inhibits apoptosis and oxidative stress of human LECs through ATM/p53 signaling pathway.