TW-37 / Ascenta - LARVOL DELTA

Chrono-Pharmacology for Cancer: Harnessing Circadian Regulations of the Cell Cycle and Immune Response Dynamics for Precision Therapy. (PubMed, ACS Pharmacol Transl Sci) - "We discussed some interesting examples, like HSP90 inhibitors (ganetespib), HDAC inhibitors (quisinostat), topoisomerase inhibitors (doxorubicin), and BCL-2 family antagonists (Obatoclax, TW-37), whose therapeutic activities are tightly regulated by circadian control over their molecular targets, pharmacokinetic processes, and downstream physiological pathways. Furthermore, the circadian influence extends to the tumor microenvironment and antitumor immunity, suggesting novel chrono-immunotherapy approaches. By putting together the molecular bases of these temporal dynamics, this review underscores the significant potential of chronotherapythe timed administration of drugs to improve cancer treatment by enhancing therapeutic indices and paving the way for personalized, temporally optimized oncology strategies."

Journal • Review • Oncology • Targeted Protein Degradation • ARNTL • BCL2 • BMAL1 • CDC37 • CDKN1A • FBXW7

TW-37, an Inhibitor of KIM-1-Mediated Endocytosis, Inhibits Cellular Senescence and Related Phenomena (KIDNEY WEEK 2025) - "Megalin expression was not changed by TW-37 treatment, suggesting that cells kept differentiation. Conclusion In the long term, TW-37 may induce anti-inflammatory and anti-aging processes in cells by suppressing KIM-1, resulting in renoprotective effects."

IO biomarker • Fibrosis • Renal Cell Carcinoma • CASP3 • EGF • IL1B • KIM1 • NLRP3 • PD-L1

PDZ-binding kinase as a prognostic biomarker for pancreatic cancer: a pan-cancer analysis and validation in pancreatic adenocarcinoma cells (PubMed, Nan Fang Yi Ke Da Xue Xue Bao) - "PBK is a key regulator of pancreatic cancer and interacts with NCAPG2 to promote tumor progression, suggesting its value as a potential biomarker and therapeutic target for pancreatic cancer."

Biomarker • IO biomarker • Journal • Pan tumor • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • CAPG • NCAPG2 • PBK

Targeting MCM10 disrupts cancer stemness and counteracts sorafenib resistance in hepatocellular carcinoma. (PubMed, Cancer Gene Ther) - "MCM10 plays a pivotal role in promoting cancer stemness and sorafenib resistance in HCC. Targeting MCM10 transcription with TW-37 represents a novel strategy to overcome sorafenib resistance and improve therapeutic outcomes in HCC patients."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • MCM10

Cardioprotection Through Pharmacological Activation of Sirtuin 5 in a Murine Model of Acute Myocardial Infarction. (PubMed, Drug Des Devel Ther) - "Co-administration of SIRT5 inhibitor, TW-37, abrogated MC3215-mediated cardioprotection. SIRT5 pharmacological agonism emerges as a novel cardioprotective target, leading to RISK pathway activation and mitochondria-related metabolic effects, converging at salvaging ischemic myocardium from I/R injury."

Journal • Preclinical • Cardiovascular • Myocardial Infarction • Myocardial Ischemia • Reperfusion Injury • MFN2 • SIRT1 • SIRT5

Comprehensive analysis of tumor immune-related gene signature for predicting prognosis, immunotherapy, and drug sensitivity in bladder urothelial carcinoma. (PubMed, Transl Cancer Res) - "Finally, 20 small molecular compounds were identified, with the TW.37 drug's half maximum inhibitory concentration (IC50) value difference being the most pronounced between the high- and low-risk patient groups, indicating its potential as a treatment option. Our constructed immune-related gene signature model forecasts BLCA patient prognosis and potentially guides individualized immunotherapy and chemotherapeutic drug choices."

Gene Signature • IO biomarker • Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • CTLA4

A High-Content and High-Throughput Imaging Screen to Identify a Small Molecule Inhibitor for the Lipid Uptake Function of KIM-1 (KIDNEY WEEK 2024) - "TW-37 is known to have Bcl2 inhibitory activity; however, this activity is likely not related to the inhibition of uptake since another specific Bcl-2 inhibitor, ABT-263, did not block ox-LDL uptake. TW-37 inhibits the oxidized lipid uptake after binding to the KIM-1 protein. Thus, TW-37 is a promising therapeutic agent for blocking lipid uptake by KIM-1 in fibrotic kidney disease."

IO biomarker • Fibrosis • Immunology • Inflammation • Nephrology • KIM1

TW-37, a Senolytic Agent and Inhibitor of KIM-1-Mediated Endocytosis, Reduces KIM-1 Expression, NF-κB-IL-1β Axis, and p16-Mediated Cellular Senescence (KIDNEY WEEK 2024) - "TW-37 as known for a senolytic and an endocytosis inhibitor for KIM-1 mediated endocytosis may induce intracellular anti-inflammatory and anti-senescence process by downregulating KIM-1, which can be renoprotective effects."

IO biomarker • Diabetes • Fibrosis • Oncology • Renal Cell Carcinoma • CASP3 • EGF • IL1B • KIM1 • NLRP3 • PD-L1

Screening for Small-Molecule Inhibitor for KIM-1 and Its Functional Validation in Kidney Fibrosis (KIDNEY WEEK 2023) - "TW-37 is known to have Bcl2 inhibitory activity; however, Bcl-2 blockade with another specific Bcl-2 inhibitor, ABT-263, did not inhibit KIM-1-dependent ox-LDL uptake, showing that the effects of TW-37 and were not related to Bcl-2 inhibition... We have identified and characterized TW-37 as an inhibitor of KIM-1 binding. Thus, TW-37 has potential use as a therapeutic for treating kidney disease where chronic KIM-1-mediated uptake of lipid-laden albumin into the proximal tubule contributes to fibrosis and CKD."

IO biomarker • Chronic Kidney Disease • Fibrosis • Immunology • Nephrology • Renal Disease • KIM1

Kidney Injury Molecule-1 Is an Independent Receptor from ACE2 for SARS-CoV-2 in Lung and Kidney (KIDNEY WEEK 2023) - "KIM-1 is an independent receptor from ACE2 for SARS-CoV-2 in the lung and kidney based on ACE2 knockout cell condition. TW-37 can be potential therapeutic agent and/or prophylactic agent for COVID-19."

Acute Kidney Injury • Infectious Disease • Nephrology • Novel Coronavirus Disease • Renal Disease • Respiratory Diseases • ACE2 • AVEN • KIM1

Repurposing of investigational cancer drugs: Early phase discovery of dengue virus NS2B/NS3 protease inhibitors. (PubMed, Arch Pharm (Weinheim)) - "Mode of inhibition experiments and computational docking analyses indicated that ABT263 and ABT737 are competitive inhibitors, whereas AT101 and TW37 are noncompetitive inhibitors of the protease. With further evaluation, the identified inhibitors of the DENV NS2B/NS3 protease have the potential to be developed into specific anti-dengue therapeutics."

Journal • Dengue Fever • Lymphoma • Oncology • BCL2

Epigenetic alternations and targeted therapy in intrauterine adhesion: A comparative study. (PubMed, Genomics) - "Five chemicals (MK-1775, PAC-1, TW-37, BIX-01294, 3-matida) were identified as putative therapeutic agents for IUA. Collectively, a series of DEGs associated with IUA were disclosed. Five chemicals and ten hub genes may be further explored as potential drugs and targets for IUA treatment."

Journal • Infertility • Sexual Disorders • CCL2 • CTGF • FOXM1 • IGF1 • IKBKB • SERPINE1 • THY1

Retinal pigment epithelium exhibits gene expression and phagocytic activity alterations when exposed to retinoblastoma chemotherapeutics. (PubMed, Exp Eye Res) - "Herein, we have developed two pluripotent stem cell (PSC)-RPE models to assess the cytotoxicity of known Rb chemotherapeutics such as Melphalan, Topotecan and TW-37. Together, our results demonstrate that although the most commonly used Rb chemotherapeutic drugs do not cause cytotoxicity in RPE, their application in vitro leads to compromised phagocytosis and strength of the barrier function, in addition to changes in gene expression that could alter the visual cycle in vivo. Our data demonstrate that widely used Rb chemotherapeutic drugs can have a deleterious impact on RPE cells and thus great care has to be exercised with regard to their delivery so the adjacent healthy RPE is not damaged during the course of tumor eradication."

Journal • Eye Cancer • Oncology • Retinal Disorders • Retinoblastoma • Solid Tumor

Exploring the robustness of DNA nanotubes framework for anticancer theranostics toward the 2D/3D clusters of hypopharyngeal respiratory tumor cells. (PubMed, Int J Biol Macromol) - "In this way, we successfully targeted 2D/3D clusters of FaDu tumor cells and achieved the tumor-specific and pH-triggered release of TW-37, causing tumor cell apoptosis. This pilot study suggests that anti-EGFR functionalized, TW-37 loaded, and cytochrome-c binding aptamer tethered DNA-NTs might be the hallmark for early tumor diagnosis and therapy."

Journal • Tumor cell • Hypopharyngeal Cancer • Oncology • BCL2 • BCL2L1 • MCL1

Codelivery of BCL2 and MCL1 Inhibitors Enabled by Phenylboronic Acid-Functionalized Polypeptide Nanovehicles for Synergetic and Potent Therapy of Acute Myeloid Leukemia. (PubMed, Adv Sci (Weinh)) - "Here, codelivery of BCL2 (ABT199) and MCL1 (TW37) inhibitors using phenylboronic acid-functionalized polypeptide nanovehicles to achieve synergetic and potent treatment of AML is adopted. In mice bearing MOLM-13-Luc or MV-411 AML cancer, NPAT reveal significant inhibition of tumor cell infiltration in bone marrow and main organs, potent suppression of tumor growth, and remarkably elevated mouse survival. With facile construction, varying drug combination, superior safety, synergetic efficacy, the phenylboronic acid-functionalized smart nanodrugs hold remarkable potential for AML treatment."

Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • BCL2 • BCL2L11

Small Molecule Screening Identifies TW-37 as a KIM-1 Inhibitor and Potential Anti-Fibrotic Molecule (KIDNEY WEEK 2022) - "TW-37 is known to have Bcl2 inhibitory activity; however, Bcl-2 blockade with another specific Bcl-2 inhibitor, ABT-263, did not inhibit KIM-1 dependent ox-LDL uptake...TW-37 protects mice from kidney fibrosis. Thus, TW-37 has potential use as a therapeutic for the treatment of kidney disease where chronic KIM-1 mediated uptake of luminal contents into the proximal tubule contributes to chronic injury and maladaptive repair."

IO biomarker • Chronic Kidney Disease • Fibrosis • Nephrology • Renal Disease • KIM1

Anticancer effects of putative and validated BH3-mimetic drugs in head and neck squamous cell carcinomas: An overview of current knowledge. (PubMed, Oral Oncol) - "One phase-II clinical trial assessing gossypol (combined with docetaxel) was found. The remaining 39 preclinical studies investigated cell lines and/or xenograft models involving the use of six validated BH3-mimetics (A-1210477, A-1331852, ABT-737, navitoclax, S63845, venetoclax) and six putative BH3-mimetics (ApoG2, gossypol, obatoclax, sabutoclax, TW-37, and YC137)...In conclusion, although clinical data are still insufficient to evaluate the anticancer effects of BH3-mimetics in head and neck squamous cell carcinomas, promising results in preclinical settings were observed concerning induction of cell death and inhibition of tumour growth. Therefore, further clinical trials are highly encouraged."

Journal • Review • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

N6-Methyladenosine-Related lncRNAs Are Novel Prognostic Markers and Predict the Immune Landscape in Acute Myeloid Leukemia. (PubMed, Front Genet) - "In addition, we discovered that the high-risk group harbored higher IC50 values of multiple chemotherapeutics and small-molecule anticancer drugs, especially TW.37 and MG.132. The present research has originated a prognostic risk model for AML according to the expression of prognostic m6A-related lncRNAs. Notably, the signature might also serve as a novel biomarker that could guide clinical applications, for example, selecting AML patients who could benefit from immunotherapy."

Biomarker • IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

pRB-Depleted Pluripotent Stem Cell Retinal Organoids Recapitulate Cell State Transitions of Retinoblastoma Development and Suggest an Important Role for pRB in Retinal Cell Differentiation. (PubMed, Stem Cells Transl Med) - "In both models, the Rb cones expressed retinal ganglion and horizontal cell markers, a novel finding, which could help to better characterize these tumors with possible therapeutic implications. Application of Melphalan, Topotecan, and TW-37 led to a significant reduction in the fraction of Rb proliferating cone precursors, validating the suitability of these in vitro models for testing novel therapeutics for Rb."

Journal • Eye Cancer • Oncology • Retinal Disorders • Retinoblastoma • Solid Tumor • RB1

ROR2 increases the chemoresistance of melanoma by regulating p53 and Bcl2-family proteins via ERK hyperactivation. (PubMed, Cell Mol Biol Lett) - "These results demonstrate that ROR2 contributes to melanoma progression by inhibiting apoptosis and increasing chemoresistance. These results not only position ROR2 as a marker of chemoresistance but also support its use as a novel therapeutic target in cancer."

IO biomarker • Journal • Melanoma • Oncology • Solid Tumor • BAX • BCL2 • BID • MCL1 • MDM2 • ROR2

[VIRTUAL] Kidney Injury Molecule 1 Is a Receptor for SARS-CoV-2 in Lung and Kidney (KIDNEY WEEK 2021) - "KIM-1-expressing HEK293 cells without ACE2 expression had increased susceptibility to infection by live SARS-CoV-2 and pseudovirions expressing spike when compared with control cells. Conclusion KIM-1 is a receptor for SARS-CoV-2 in the lung and kidney and thus, KIM-1 inhibitors such as TW-37 can be potential therapeutics and/or prophylactic agents for COVID-19."

Acute Kidney Injury • Hepatology • Infectious Disease • Inflammation • Nephrology • Novel Coronavirus Disease • Renal Disease • Respiratory Diseases • KIM1

Transformation of the Plastid Genome in Tobacco: The Model System for Chloroplast Genome Engineering. (PubMed, Methods Mol Biol) - "Petit Havana and N. sylvestris accession TW137 are similar. Plastid transformation in a subset of N. tabacum cultivars and in Nicotiana benthamiana requires adjustment of the tissue culture protocol. We describe updated vectors targeting insertions in the unique and repeated regions of the plastid genome, vectors suitable for regulated gene expression by the engineered PPR10 RNA binding protein as well as systems for marker gene excision."

Journal

KIM-1 mediates fatty acid uptake by renal tubular cells to promote progressive diabetic kidney disease. (PubMed, Cell Metab) - "We also identified TW-37 as a small molecule inhibitor of KIM-1-mediated PA-albumin uptake and showed in vivo in a kidney injury model in mice that it ameliorates renal inflammation and fibrosis. Together, our findings support KIM-1 as a new therapeutic target for DKD."

Journal • Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Fibrosis • Glomerulonephritis • Immunology • Inflammation • Metabolic Disorders • Nephrology • Renal Disease • KIM1

Preclinical analysis of novel prognostic transcription factors and immune-related gene signatures for bladder cancer via TCGA-based bioinformatic analysis. (PubMed, Oncol Lett) - "It was then verified that downregulation of FOSL1 can lead to an enhanced sensitivity of the TW37 in T24 bladder cancer cells. Overall, the present prognostic model demonstrated a robust capability of predicting OS of patients with BLCA. Hence, the gene markers identified could be applied for targeted therapies against BLCA."

Journal • Preclinical • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • CD8 • CXCL13 • EGR1 • EREG

Synergistic Effects of TW-37 and ABT-263 on Renal Cell Carcinoma Cells. (PubMed, Cancer Manag Res) - "Finally, TW-37 and ABT-263 also synergistically repressed the growth of RCC cells in xenograft mice. In summary, our data demonstrated that combined treatment with TW-37 and ABT-263 exhibited synergistic RCC cell death and this combination may be applied as an effective therapeutic strategy against RCC."

Journal • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Urethral Cancer • Urology • BCL2