tandutinib (MLN518) / Takeda - LARVOL DELTA

High-throughput screening uncloaks actionable compounds for ttmv::rara AML (ASH 2025) - "Clinical data from ourmulticenter cohorts (n=25) revealed that 20 patients showed initial response to conventional APLregimens including all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), but paradoxicallydemonstrated poor disease control, evidenced by the event-free survival (EFS) was 53.6% with relapse-free survival (RFS) exceeding to 53.8% beyond 2 years...Dose-response curves revealed significant half maximalinhibitory concentration (IC50) reductions (>5-fold) relative to vector controls in 5/10 candidates:anagrelide (phosphodiesterase III inhibitor), lenvatinib (multi-kinase inhibitor), cytarabine (nucleosideanalog), cyclocytidine (prodrug of cytarabine), and tandutinib (FLT3 inhibitor). Crucially, the establishedAPL therapies ATRA and ATO, as well as the widely used BCL2 inhibitor venetoclax, showed no significantreduction in IC50, suggesting a possible link to the clinical observation of rapid relapse in this disease.Our findings establish the human..."

Acute Myelogenous Leukemia • Acute Promyelocytic Leukemia • Hematological Malignancies • Leukemia • CD33 • CD34 • CEACAM8 • FLT3 • ITGAM • PTPRC

FLT3-ITD Driven CMTM6 Expression Contributes to Immune Escape of Acute Myeloid Leukemia (ASH 2024) - "FLT3 kinase inhibition assays were performed using the FLT3 inhibitors tandutinib, crenolanib, and quizartinib. Taken together, our study identifies a new mechanism of oncogene-induced stabilization of CMTM6 in leukemia cells, resulting in tumor immune escape. Inhibiting the CMTM6/PD-L1 axis could enhance the GVL effect post allo-HCT in patients with FLT3-ITD+ AML."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • CD34 • CD69 • CD8 • CMTM6 • FLT3 • IFNG

FLT3-ITD Induces CMTM6 and Enhances Immune Escape in Acute Myeloid Leukemia. (PubMed, Cancer Res) - "Furthermore, combination therapy with anti-PD-L1 and tandutinib significantly improved survival, suppressed leukemia cell expansion, and augmented the anti-leukemia T cell response in mice bearing FLT3-ITD+ leukemia...Furthermore, CMTM6 upregulation and protein interaction with FLT3 was validated in primary leukemia cells from two independent cohorts of patients with FLT3-ITD+ AML. Collectively, these findings uncover FLT3-mediated stabilization of CMTM6 in AML cells, which results in enhanced PD-L1 cell surface expression and leukemia immune escape."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • Transplantation • CMTM6 • FLT3

Signature of leukemia stem cell death pattern predicts prognosis and therapeutic response of acute myeloid leukemia patients. (PubMed, Sci Rep) - "Additionally, predictions regarding FDA-approved drugs indicated that the high LSCD score group is less sensitive to Venetoclax but more sensitive to Crenolanib, Tandutinib, or Midostaurin. In summary, we developed an LSCD model that shows the predictive potential of clinical prognosis and drug sensitivity. This model provides meaningful insights for personalized treatment of AML patients."

Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • CDK6 • HOXA9 • IL2RA • S100A4 • XIRP2

Intratumoral core microbiota predicts prognosis and therapeutic response in gastrointestinal cancers. (PubMed, Microbiol Spectr) - "Additionally, we identify XL999 and tandutinib as potential therapies for high-risk patients and reveal that microbiota composition correlates with immunotherapy response. By integrating microbiome profiling into cancer prognosis and treatment selection, this study offers a novel strategy for precision oncology, advancing microbial biomarkers for risk assessment, drug selection, and personalized immunotherapy."

IO biomarker • Journal • Gastrointestinal Cancer • Oncology • Solid Tumor • KRAS

Efficacy and safety of FLT3 inhibitors in monotherapy of hematological and solid malignancies: a systemic analysis of clinical trials. (PubMed, Front Pharmacol) - " We searched and reviewed clinical trial reports on the monotherapy of 13 FLT3 inhibitors, including sorafenib, lestaurtinib, midostaurin, gilteritinib, quizartinib, sunitinib, crenolanib, tandutinib, cabozantinib, pexidartinib, pacritinib, famitinib, and TAK-659 in patients with hematological and solid malignancies before May 31, 2023...The ORRs of FLT3 inhibitors in hematologic malignancies and solid tumors were 40.8% and 18.8%, respectively, indicating FLT3 inhibitors were more effective for hematologic malignancies than for solid tumors. In addition, time to maximum plasma concentration (Tmax) in these FLT3 inhibitors ranged from 0.7-12.0 hours, but the elimination half-life (T1/2) range was highly variable, from 6.8 to 151.8 h. FLT3 inhibitors monotherapy has shown significant anti-tumor effect in clinic, and the effectiveness may be further improved through combination medication."

Monotherapy • Review • Acute Myelogenous Leukemia • Dermatology • Febrile Neutropenia • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Leukemia • Neutropenia • Oncology • Solid Tumor • Thrombocytopenia • FLT3

Identification of potential RapJ hits as sporulation pathway inducer candidates in Bacillus coagulans via structure-based virtual screening and molecular dynamics simulation studies. (PubMed, J Mol Model) - "Based on the binding compartment, through molecular docking, MD simulation, hydrogen bonds, and binding-free energy calculations, a series of novel hits against RapJ named tandutinib, infigratinib, sitravatinib, linifanib, epertinib, surufatinib, and acarbose were identified. Consequently, acarbose is probably the most suitable hit for RapJ enzyme. Notably, experimental validation is crucial to confirm the effectiveness of the selected ligands."

Journal

LAM-003, a Novel Oral Heat Shock Protein 90 Inhibitor for Treatment of Acute Myeloid Leukemia, Including Wild-Type and FMS-like Tyrosine Kinase 3 (FLT3)-Mutant Disease (ASH 2019) - P1; "Moreover, BA/F3 cells expressing FLT3-ITD and the F691L mutation exhibited the expected resistance to crenolanib, yet LAM-003 retained anti-proliferative activity. Additionally, MOLM-13 cells harboring a FLT3 D835Y mutation demonstrated expected resistance to the FLT3i sorafenib and tandutinib yet remained sensitive to LAM-003...Synergy was demonstrated with FLT3i, daunorubicin, azacitidine or cytarabine, with the most robust synergy being observed with venetoclax...These nonclinical studies demonstrate that LAM-003 exhibits antileukemic activity, overcomes mechanisms of FLT3i resistance and potently synergizes with existing AML drugs. As such, our data provide strong rationale for evaluation of LAM-003 in an ongoing clinical trial in patients with AML (NCT03426605)."

IO biomarker • Acute Myelogenous Leukemia • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • FLT3 • GSK3B

Esterase-responsive and size-optimized prodrug nanoparticles for effective intracranial drug delivery and glioblastoma treatment. (PubMed, Nanomedicine) - "Here, we report a tandutinib-based prodrug (proTan), which responds to the GBM microenvironment, that was combined with NPs to overcome the BBB. AMD3100-PLGA NPs loaded with proTan inhibited tumor growth and effectively prolonged the survival of tumor-bearing mice."

Journal • Brain Cancer • Glioblastoma • Immunology • Oncology • Solid Tumor

A Systematic Review and Meta-Analysis Comparing Type I and II FLT3 Inhibitors in Relapsed/ Refractory Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome (ASH 2021) - "Giltertinib (n=3 studies) was the most frequently studied type 1 inhibitor, and quizartinib (n=6) and sorafenib (n=5) were the most frequently studied type 2 inhibitors...The highest ORR was for gilteritinib (68%; 95% CI, 61-73%) among type 1 and sorafenib (99%; 95% CI, 81-100%), linifanib (99%; 95% CI, 89-100%), and tandutinib (100%; 95% CI, 93-100%) for type 2 (Fig...The highest CRc was for midostaurin (98%; 95% CI, 79-100%) among type 1 and sorafenib (97%; 95% CI, 68-100%), tandutinib (98%; 95% CI, 72-100%), and semaxinib (98%; 78-100%) among type 3 (Fig... Both type 1 and 2 inhibitors are effective as monotherapy in R/R AML and HR-MDS patients. Though not statistically significant, better ORR for type 2 than for type 1 inhibitors in the R/R setting provides a Background to explore the biological heterogeneity of response and preferential sensitivity to ITD-targeted therapy alone rather than the dual inhibitor. More prospective randomized study designs comparing type..."

Retrospective data • Review • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation • FLT3

CCT245718, a dual FLT3/Aurora A inhibitor overcomes D835Y-mediated resistance to FLT3 inhibitors in acute myeloid leukaemia cells. (PubMed, Br J Cancer) - "Our results demonstrate that CCT245718 is a potent dual FLT3/Aurora A inhibitor that can overcome TKD-mediated acquired resistance."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BIRC5 • FLT3 • STAT5

Identification and characterization of in vitro, in vivo, and reactive metabolites of tandutinib using liquid chromatography ion trap mass spectrometry. (PubMed, Anal Methods) - "The formed reactive intermediates may be the reason behind TND toxicity. In silico toxicological studies were performed for TND and its related (in vitro and in vivo) metabolites were evaluated using the DEREK software tool."

Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

[VIRTUAL] The Combined Treatment with the FLT3-Inhibitor AC220 and the Complex I Inhibitor Iacs-010759 Synergistically Depletes Wt- and FLT3-Mutated Acute Myeloid Leukemia Cells (ASH 2020) - "1C) are known FLT3 (FMS-like tyrosine kinase 3) inhibitors, including AC220 (quizartinib), dovitinib, nintedanib, SGI-1776, and rebastinib, pointing to a molecular target of great potential interest in the design of synergistic drug combinations with IACS-010759. Thus, we investigated more in-depth the synergism between IACS-010759 (10nM) and 13 FLT3 inhibitors, all currently in clinical trials (AC220, sorafenib, gilteritinib, sunitinib, ponatinib, midostaurin, ibrutinib, TP-0903, crenolanib, tandutinib, FF-10101, lestaurtinib, and KW-2449; 0.0128:5x:5000nM), in AML cell lines (FLT3-wt KG-1, U937, OCI-AML2, OCI-AML3; and FLT3-mutant MOLM-13 and MOLM-14)...Influx inhibition of both the two main carbon sources, glucose and glutamine, was observed leading to impairment of the TCA cycle and glycolysis for energy production, as well as pentose phosphate pathway and de novo nucleotide biosynthesis. In conclusion, we identified a novel drug combination AC220 and IACS-010759..."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Metabolic Disorders • Oncology • FLT3

LC-MS/MS Estimation of the Anti-Cancer Agent Tandutinib Levels in Human Liver Microsomes: Metabolic Stability Evaluation Assay. (PubMed, Drug Des Devel Ther) - "TND and entrectinib (ENC) (internal standard; IS) were resolved using an isocratic elution system with a reversed stationary phase (C column). TND exhibited a moderate extraction ratio indicative of good bioavailability. According to the literature, the approach developed in the present study is the first established LC-MS/MS method for assessing TND metabolic stability."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Joint efforts of 3 institutions discover prognostic biomarker for brain cancer (Korea Biomedical Review) - "Severance Hospital said it and two other institutions have jointly developed a biomarker and treatment for predicting the prognosis of glioblastoma, incurable cancer...'For GPC1 tumor-derived cancer cells, treatments such as vistusertib, tandutinib, and crizotinib showed high treatment response, while hedgehog inhibitor erismodegib and the pan-ERBB inhibitor canertinib showed high treatment response for GPC2,' the teams said. 'Notably, in the PHGDH-negative patient group, predicted to have the worst prognosis, the mTORC1/2 dual inhibitor vistusertib showed a good therapeutic'."

Biomarker • Glioblastoma • Oncology

[VIRTUAL] DrugCell: A visible neural network to guide personalized medicine (AACR-II 2020) - "Consistent with these inferences, combinations of etoposide with an AKT, MEK or HDAC inhibitor were highly synergistic across multiple cell lines...DrugCell suggested combinations of sorafenib and DNA damaging agents or tandutinib and PI3K/MTOR inhibitors to be effective combination therapies in this leukemia cohort...Lastly, DrugCell was able to accurately suggest effective and ineffective drug combinations in a pan-cancer PDX tumor cohort and significantly improve progression-free survival compared to monotherapy. DrugCell serves as an important step towards next generation intelligent systems in drug discovery and personalized medicine."

Hematological Malignancies • Leukemia • Oncology

FLT3 inhibitors in acute myeloid leukemia. (PubMed, J Hematol Oncol) - "In this review, we summarized the preclinical and clinical studies on new FLT3 inhibitors, including sorafenib, lestaurtinib, sunitinib, tandutinib, quizartinib, midostaurin, gilteritinib, crenolanib, cabozantinib, Sel24-B489, G-749, AMG 925, TTT-3002, and FF-10101. New generation FLT3 inhibitors and combination therapies may overcome resistance to first-generation agents."

Journal • Review

DrugCell: A visible neural network to guide precision medicine (AACR-NCI-EORTC 2019) - "Accordingly, combination of paclitaxel with the mTOR inhibitor, MK8669, was highly synergistic across multiple cell lines...In support of these mechanisms, combination of etoposide, a topoisomerase II inhibitor, with AKT or MEK inhibitors (downstream of the cholinergic receptor) or the HDAC inhibitor vorinostat were highly synergistic across multiple cell lines...Finally, we used DrugCell to predict effective therapeutic combinations for acute myeloid leukemia patients, leading to identification of drug combinations currently in clinical trials including lenalidomide + DNMT inhibitors and tandutinib + PI3K/MTOR inhibitors. Armed with interpretability and generalizability, DrugCell serves as an important step towards a next generation of intelligent systems in drug discovery and precision medicine."

BRCA Biomarker • BRCA1

Discovery of 4-piperazinyl-2-aminopyrimidine derivatives as dual inhibitors of JAK2 and FLT3. (PubMed, Eur J Med Chem) - "In this study, we assembled the pharmacophores of momelotinib and tandutinib to get a series of 4-piperazinyl-2-aminopyrimidine derivatives. Compound 14j showed the most balanced in vitro inhibitory activity against JAK2 and FLT3 (JAK2 IC = 27 nM, FLT3 IC = 30 nM), and it also showed potent inhibition against the above tested cell lines. In the cellular context, 14j strongly induced apoptosis by arresting cell cycle in the G/S phase, and was selected as a promising JAK2/FLT3 dual inhibitor."

Journal

Midostaurin reduces Regulatory T cells markers in Acute Myeloid Leukemia. (PubMed, Sci Rep) - "We examined the effect of four different FLT3 inhibitors (midostaurin, sorafenib, tandutinib, and quizartenib) on T cell populations in peripheral blood mononuclear cells (PBMC) obtained from healthy donors and from patients with AML. Interferon-γ(IFN-γ), tumor necrosis factor-α(TNF-α), and IL-10 levels were also reduced following midostaurin treatment. Considering the FDA approval of midostaurin for use in patients with AML in the pre-transplant setting, our finding will have important clinical implication as it provides the rationale for functional investigation of the use of midostaurin in post-transplant patients."

Journal

Gilteritinib: a novel FLT3 inhibitor for acute myeloid leukemia. (PubMed, Biomark Res) - "Multiple FLT3 inhibitors are in clinical development, including lestaurtinib, tandutinib, quizartinib, midostaurin, gilteritinib, and crenolanib. Currently, multiple clinical trials are ongoing to evaluate the combination of gilteritinib with other agents and regimens. This study summarized clinical trials of gilteritinib for AML."

Biomarker • Journal • Review