DT-061 / University of Maryland - LARVOL DELTA

Protein phosphatase 2A, a critical modulator of cardiomyocyte ferroptosis in takotsubo syndrome (AHA 2025) - "Furthermore, administration of an orally bioavailable small molecule activator of PP2A, DT-061, strongly mitigated myocardial damage and improved cardiac function in TTS mice. These results demonstrate that PP2A plays a critical role in protecting against cardiac ferroptosis and acute heart failure, thereby providing a novel pharmacological therapy for the prevention and treatment of TTS."

Late-breaking abstract • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure

PTPN12 Is Targetable and Context-Specific TSG in -7/del7q Myeloid Neoplasia (ASH 2024) - "To directly assay the effects of PTPN12's phosphatase activity of cell-signaling, we utilized the phosphatase activator DT-061 in models of del7q MN (KG1, featuring low PTPN12 expression), -7 MN (F36P, featuring moderate PTPN12 expression), and chromosome 7 diploid MN (THP1, featuring high PTPN12 expression)...Together, these results indicate that PTPN12 may be a critical TSG contributing to -7/del7q leukemogenesis. As an overlooked contributor to -7del7q leukemogenesis, PTPN12 may represent a small-molecule targetable therapeutic option for a patient population in dire need."

Acute Myelogenous Leukemia • Anemia • Aplastic Anemia • Bladder Cancer • Brain Cancer • Breast Cancer • CNS Tumor • Genito-urinary Cancer • Glioblastoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lung Cancer • Myeloproliferative Neoplasm • Non Small Cell Lung Cancer • Oncology • Osteosarcoma • Prostate Cancer • Sarcoma • Solid Tumor • Triple Negative Breast Cancer • Urothelial Cancer • GLI2 • PTPN1 • PTPN12

PP2A Promotes Epithelial-Mesenchymal Transition in Chronic Rhinosinusitis with Nasal Polyps via Wnt/β-Catenin Pathway: A Novel Insight. (PubMed, J Asthma Allergy) - "The rhWNT3A-induced EMT cell model using BEAS-2B cell line was established in vitro and treated with either LB-100 or the PP2A agonist DT-061...PP2A exerts a positive regulatory effect on the modulation of Wnt signaling in CRSwNP. Targeting PP2A might represent a viable therapeutic option for treating CRSwNP."

Journal • Chronic Rhinosinusitis With Nasal Polyps • Immunology • Inflammation • Nasal Polyps • Otorhinolaryngology • Respiratory Diseases • Sinusitis • WNT3A

PP2A Attenuates Thoracic Aneurysm and Dissection in Mouse Models of Marfan Syndrome. (PubMed, Hypertension) - "Mechanistic studies suggest that DT-061 suppresses mTOR signaling and smooth muscle cell dedifferentiation, contributing to its effects on thoracic aortic aneurysm and dissection progression. These studies demonstrate a pathological role of PP2A activity loss in the cause of MFS and implicate that activation of PP2A may serve as a novel therapeutic strategy to limit MFS progression, including aortic aneurysm formation."

Journal • Preclinical • Cardiovascular • Genetic Disorders

Protocadherin-7 Regulates Monocyte Migration Through Regulation of Small GTPase RhoA and Rac1. (PubMed, Int J Mol Sci) - "Treatment with the PP2A-specific activator DT-061 enhanced cell migration, whereas treatment with the GSK3β-specific inhibitor AR-A014418 inhibited migration in wild-type monocytes...Taken together, these results indicate that Pcdh7 regulates monocyte migration through the activation of RhoA and Rac1. Given the pivotal role of cell migration in both physiological and pathological processes, our findings provide a foundation for future research into therapeutic strategies targeting Pcdh7-regulated migration."

Journal • CDH23 • PCDH • RAC1 • RHOA

IL-17A's role in exacerbating radiation-induced lung injury: Autophagy impairment via the PP2A-mTOR pathway. (PubMed, Biochim Biophys Acta Mol Cell Res) - "IL-17A inhibits autophagy in RILI through the PP2A B56α-mTOR pathway, exacerbating lung damage. Further research is needed to clarify the role of IL-17A in different cell types and conditions. Targeting the IL-17A-PP2A B56α-mTOR axis may offer new therapeutic strategies for RILI management."

Journal • Respiratory Diseases • IL17A

Protein Phosphatase 2A Activation Promotes Heart Transplant Acceptance in Mice. (PubMed, Transplantation) - "PP2A activation prevents cardiac rejection and prolongs allograft survival in a murine model. Our findings highlight the potential of PP2A activation in improving alloengraftment in heart transplantation."

Journal • Preclinical • Cardiovascular • Congestive Heart Failure • Heart Failure • Immunology • Inflammation • Transplant Rejection • Transplantation • CTLA4

PP2A-Mediated GSK3β Dephosphorylation Is Required for Protocadherin-7-Dependent Regulation of Small GTPase RhoA in Osteoclasts. (PubMed, Cells) - "On the other hand, DT-061 treatment rescued impaired RhoA activation and RANKL-induced osteoclast differentiation in Pcdh7 cells. Taken together, these results demonstrate that PP2A dephosphorylates GSK3β and thereby activates it in a Pcdh7-dependent manner, which is required for activation of small GTPase RhoA and proper osteoclast differentiation."

Journal • CDH23 • GSK3B • PCDH • RAC1 • RHOA

PP2A-based triple-strike therapy overcomes mitochondrial apoptosis resistance in brain cancer cells. (PubMed, Mol Oncol) - "In contrast, all tested brain tumor cell models were sensitive to a triplet therapy, in which AKT and PDK inhibition was combined with the pharmacological reactivation of protein phosphatase 2A (PP2A) by NZ-8-061 (also known as DT-061), DBK-1154 and DBK-1160...Mechanistically, PP2A reactivation converted the cytostatic AKTi + PDKi response to cytotoxic apoptosis, through PP2A-elicited shutdown of compensatory mitochondrial oxidative phosphorylation and by increased proton leakage. These results encourage the development of triple-strike strategies targeting mitochondrial metabolism to overcome therapy tolerance in brain tumors."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Medulloblastoma • Oncology • Solid Tumor

PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis. (PubMed, J Clin Invest) - "Targeted therapies such as venetoclax (Bcl-2 inhibitor) have revolutionized the treatment of chronic lymphocytic leukemia (CLL). DT-061 inhibited the growth of wild type and Bax/Bak double knockout multidrug resistant CLL cells in a xenograft mouse model. Collectively, we discovered multidrug resistant CLL cells in patients, and validated a pharmacologically tractable pathway to deplete this reservoir."

Journal • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • BCL2L1 • MCL1

Effects of PP2A-activating drugs on FLT3 inhibitor resistance mediated by diverse mechanisms in acute myeloid leukemia with FLT3-ITD (AACR 2023) - "Additionally, while FTY720, but not DT-061, markedly sensitized M14(R)701 cells to quizartinib and gilteritinib, FTY720 and DT-061 increased phosphatase activity similarly in a PP2A immunoprecipitation phosphatase assay, indicating that sensitization by FTY720 likely occurs by a mechanism other than PP2A activation. Potential induction of ceramide accumulation by FTY720, a sphingolipid analog, in M14(R)701 cells is being studied."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • MYC • NRAS • PIM1

GATA1-Dependent Ceramide Homeostasis Controls Cytokine Signaling and Erythroid Cell Function (ASH 2022) - "Furthermore, two distinct PP2A activators, FTY-720 and DT-061, impacted SCF and Epo-dependent signaling similar to C6-Cer, suggesting that ceramide inhibits cytokine signaling via activation of PP2A. These findings establish a paradigm in which GATA1 controls sphingolipid biosynthetic enzymes and the generation of regulatory lipids that restrict cytokine signaling, thereby impacting erythrocyte development and function. As inflammatory mediators implicated in anemia of inflammation elevate dihydroceramides and ceramides, we propose that the integrated transcriptional, metabolic and signaling mechanism has broad importance in erythroid biology and pathology."

Anemia • Hematological Disorders • Immunology • Inflammation • ER • GATA1 • KIT • STAT5

Protein Phosphatase 2a Inhibits Gastric Cancer Cell Glycolysis by Reducing MYC Signaling. (PubMed, Cell Biochem Biophys) - "Importantly, inhibition of PP2A activity by genetic silencing of PPP2R5A resulted in a growth advantage, which can be largely compromised by the addition of the glycolysis inhibitor 2-Deoxy-D-glucose, suggesting a glycolysis-dependent effect of PP2A in gastric cancer...Ectopic expression of a phosphorylation-mutant c-Myc resistant to PP2A (MycT58A) restored the inhibitory effect of FTY-720 and DT-061 on lactate production and glucose uptake. Furthermore, there was a close association between SET and CIP2A expression and c-Myc gene signatures in gastric cancer samples. Collectively, this study provides strong evidence of the involvement of PP2A in the Warburg effect and indicates that it could be a novel antitumor strategy to target tumor metabolism in gastric cancer."

Journal • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CIP2A • MYC

GSK3β is a critical, druggable component of the network regulating the active NOTCH1 protein and cell viability in CLL. (PubMed, Cell Death Dis) - "Notably, for PP2A activation, we used the highly specific activator DT-061, that also reduces leukemic burden in peripheral blood, spleen and bone marrow in the Eµ-TCL1 adoptive transfer model of CLL, with a concomitant decrease in N1-ICD expression. Overall, we identify in GSK3β a key component of the network regulating N1-ICD stability in CLL, and in AKT and PP2A new druggable targets for disrupting NOTCH1 signaling with therapeutic potential."

Journal • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • GSK3B • NICD • NOTCH1

Chemogenetic profiling reveals PP2A-independent cytotoxicity of proposed PP2A activators iHAP1 and DT-061. (PubMed, EMBO J) - "In contrast, DT-061 disrupts both the Golgi apparatus and the ER and lipid synthesis associated with these structures. Our work provides insight into the biological pathways perturbed by iHAP1 and DT-061 causing cellular toxicity and argues that these compounds cannot be used for dissecting PP2A-B56 biology."

Journal • Oncology

Potential of phenothiazines to synergistically block calmodulin and reactivate PP2A in cancer cells. (PubMed, PLoS One) - "Here we examined the potential of the PTZ fluphenazine (Flu) and its mustard derivative (Flu-M) to synergistically act on two cancer associated targets, calmodulin (CaM) and the tumor suppressor protein phosphatase 2A (PP2A). Benchmarking against the KRAS-G12C specific inhibitor AMG-510 in MIA PaCa-2 cells revealed a higher potency of Flu-M than combinations of DT-061 and a CaM inhibitor on MAPK-output and a strong effect on cell proliferation. While our study is limited, our results suggest that improved PTZ derivatives that retain both, their CaM inhibitory and PP2A activating properties, but have lost their neurological side-effects, may be interesting to pursue further as anti-cancer agents."

Journal • CNS Disorders • Oncology • BRAF • KRAS • MYC

Targeting Translational Control in Cancer Using Small Molecule Activators of PP2A. (PubMed, FASEB J) - "SMAPs promote PP2A-dependent proteasomal degradation of Snail/Slug protein via a non-canonical mechanism, as well as upregulation of ATF4. We propose that these effects relieve transcriptional repression of 4E-BP1 by Snail/Slug while promoting 4E-BP1 transcription by ATF4, leading to a robust increase in 4E-BP1 levels. 4E-BP1 translation repressive activity is ensured by PP2A-induced 4E-BP1 dephosphorylation. Thus, SMAPs offer a powerful tool for therapeutic targeting of aberrant protein translation in cancer."

Journal • Oncology • ATF4 • EIF4E • EIF4EBP1 • EIF4G1 • PKD1 • PRKD1 • SNAI2

Activation of PP2A-B56α Heterocomplex Synergizes with Venetoclax Treatment in Acute Myeloid Leukemia through Modulation of BCL-2 and MCL-1 (ASH 2021) - "Recently, the BCL-2 inhibitor venetoclax combined with either hypomethylating agents or low-dose cytarabine has been approved to treat elderly or unfit AML patients...Mechanistically, FTY720 and venetoclax co-treatment promoted a synergistic pro-apoptotic activity by increasing significantly the activity of caspases 3/7 and decreasing the mitochondrial membrane potential ( Fig...Combining DT-061 and venetoclax resulted in similar synergistic effects, proving that the PP2A-B56α complex is crucial for the combination therapy ( Fig...We also prove that the B56α regulatory subunit of PP2A is a key determinant of the synergistic pro-apoptotic effect through modulation of BCL-2 and MCL-1 activities. Therefore, our preclinical results support the rationale for combining these targeted therapies in the treatment of AML."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • CASP7 • MCL1

Cyclin G2 promotes the formation of smooth muscle cells derived foam cells in atherosclerosis via PP2A/NF-κB/LOX-1 pathway. (PubMed, Ann Transl Med) - "DT-061 an activator of PP2A (protein phosphatase 2A) agonist was used to verify the role of PP2A in the process...This led to decreased lipid endocytosis reducing the formation of VSMCs- derived foam cells. Cyclin G2 increases the nuclear translocation of p-NF-κB by reducing the enzymatic activity of PP2A and upregulating LOX-1, thereby promotes the formation of VSMCs -derived foam cells in atherosclerosis."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • APOE

SWATH-MS proteomics of PANC-1 and MIA PaCa-2 pancreatic cancer cells allows identification of drug targets alternative to MEK and PI3K inhibition. (PubMed, Biochem Biophys Res Commun) - "PP2A activator DT-061 decreased viability of PANC-1 cells and this was accompanied by reduced expression of c-Myc. PANC-1 cells also showed response to metformin and the novel complex I inhibitor IACS-010759. These findings provide insights into the distinct cellular proteomes and point out alternative pharmacological targets for MEK and PI3K inhibition-resistant pancreatic cancer cells."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • KRAS • MYC