APTO-253 / Aptose Biosci - LARVOL DELTA

Induction of T-Cell Differentiation by KLF4 in T-Cell Acute Lymphoblastic Leukemia Cells Harboring Activating Mutation in NOTCH3. (PubMed, FASEB J) - "Furthermore, we found that APTO-253, a small-molecule inducer of KLF4, effectively suppressed cell growth in TALL-1 cells by promoting T-cell differentiation followed by apoptotic cell death. These findings suggest a promising strategy for developing novel differentiation therapies for T-ALL with NOTCH3 mutations."

Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma • CD4 • CD8 • KLF4 • NOTCH3

Cell type-specific upregulation of NKG2D ligand MICA in response to APTO253. (PubMed, Ann Transl Med) - "Additionally, our data suggest a link between the induced expression of MICA and the regulation of both, KLF4 and c-MYC, which might represent a mechanism underlying the induction of NKG2D-L expression upon treatment with APTO253. These results may contribute to the potential use of APTO253 as a treatment to improve tumor cell-mediated NK cell cytotoxicity in various cancers."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Hepatology • Leukemia • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • KLF4 • MICA • MYC • NKG2D

Downregulated KLF4, induced by m6A modification, aggravates intestinal barrier dysfunction in inflammatory bowel disease. (PubMed, Cell Mol Life Sci) - "Our study demonstrated that KLF4 is a crucial regulator of IEB, suggesting that targeting KLF4 may be a promising therapeutic alternative for IBD."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • ALKBH5 • KLF4 • METTL3 • YTHDF2

KLF4 Drives Fibroblast Activation to Promote Kidney Fibrosis via YAP Signaling (KIDNEY WEEK 2024) - "Conversely, the KLF4 agonist Apto253 enhanced fibroblast activation induced by TGFβ1... These findings suggest that KLF4 significantly promotes fibroblast activation and kidney fibrogenesis potentially through activating the YAP singling pathway. Targeting this singling pathway may shine light on ways to protect against kidney fibrosis in patients with chronic kidney diseases."

Cardiovascular • Chronic Kidney Disease • Fibrosis • Immunology • Nephrology • Renal Disease • Reperfusion Injury • KLF4 • TGFB1

Quercetin Attenuates KLF4-Mediated Phenotypic Switch of VSMCs to Macrophage-like Cells in Atherosclerosis: A Critical Role for the JAK2/STAT3 Pathway. (PubMed, Int J Mol Sci) - "In contrast, APTO-253, a KLF4 activator, was found to reverse the effects of quercetin...These effects were significantly mitigated by quercetin but exacerbated by coumermycin A1, a JAK2 activator. Our research illustrates that quercetin inhibits the KLF4-mediated phenotypic switch of VSMCs to macrophage-like cells and reduces atherosclerosis by suppressing the JAK2/STAT3 pathway."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • APOE • CD68 • KLF4 • LGALS3

Aptose Reports Results for the First Quarter 2024 (GlobeNewswire) - "Luxeptinib program costs were $208,000 and decreased by approximately $1.1 million, primarily due to lower clinical trial and manufacturing costs associated with the conclusion of certain luxeptinib clinical trial activities. Program costs for APTO-253 were $22,000. The Company decided on December 20, 2021 to discontinue further development of APTO-253."

Commercial • Discontinued • Hematological Malignancies • Oncology • Solid Tumor

Comprehensive analysis of ATP6V1s family member, ATP6V1C2, with prognostic and drug development values in colorectal cancer. (PubMed, Pathol Res Pract) - "CellMiner explore told us LOR-253 and Sonidegib may be effective in CRC cancer treatment. In summary, ATP6V1C2 may be a new therapeutic target for CRC. The illustration is shown in Figure 9."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

MicroRNA-145 Gene Modification Enhances the Retention of Bone Marrow-Derived Mesenchymal Stem Cells within Corpus Cavernosum by Targeting Krüppel-Like Factor 4. (PubMed, World J Mens Health) - "Overall, miR-145 modification prolongs the retention of the transplanted BMSCs within the CC, and this effect might be attributed to the modulation of the miR-145/KLF4 axis. Consequently, our findings offer a promising and innovative strategy to enhance the local stem cell-based treatments."

Epigenetic controller • Journal • Erectile Dysfunction • Transplantation • CD31 • KLF4 • MIR145 • PECAM1

Suppression of super-enhancer-driven TAL1 expression by KLF4 in T-cell acute lymphoblastic leukemia. (PubMed, Oncogene) - "In addition, we found that APTO-253, a small molecule inducer of KLF4, exerts an anti-leukemic effect by targeting SE-driven TAL1 expression in T-ALL cells. Taken together, our results suggest that the induction of KLF4 is a promising strategy to control TAL1 expression and could be a novel treatment for T-ALL patients with a poor prognosis."

Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • KLF4 • MYB • TAL1

Suppression of Super-Enhancer-Driven TAL1 Expression By KLF4 in T-Cell Acute Lymphoblastic Leukemia (ASH 2023) - "Finally, we investigated whether pharmacological induction of KLF4 using APTO-253, a small-molecule inducer of KLF4, could control leukemia...Moreover, pharmacological induction of KLF4 demonstrated anti-leukemic activity in T-ALL cells. These findings propose a promising strategy for patients with T-ALL and 5' TAL1 SE."

IO biomarker • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • BCL2 • BCL2L1 • KLF4 • MYB • TAL1

Aptose Reports Results for the Third Quarter 2023 (Aptose Biosci Press Release) - "Aptose Biosciences Inc...announced financial results for the three months and nine months ended September 30, 2023, and provided a corporate update...Program costs for tuspetinib were $5.8 million for the three-month period ended September 30, 2023. The higher program costs for tuspetinib in the current period represent the enrollment of patients in our APTIVATE clinical trial, our healthy volunteer trial, manufacturing activities to support clinical development, and related expenses; Program costs for luxeptinib decreased by approximately $742 thousand, primarily due to lower clinical trial costs and lower manufacturing costs as a result of the current formulation requiring less API than the prior formulation; Program costs for APTO-253 decreased by approximately $64 thousand, due to the Company’s decision on December 20, 2021 to discontinue further clinical development of APTO-253."

Commercial • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Cuproptosis-Related Genes MTF1 and LIPT1 as Novel Prognostic Biomarker in Acute Myeloid Leukemia. (PubMed, Biochem Genet) - "In addition, APTO-253 has the potential to become an AML-targeted drug. The cuproptosis-related genes MTF1 and LIPT1 can be used as prognostic biomarkers in AML. A total of six lncRNAs, including MALAT1, are involved in the expression and regulation of MTF1 in AML through six miRNAs such as hsa-miR-32-5p."

Biomarker • Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • ATP7B • CDKN2A • DLAT • FDX1 • FLT3 • HP • IDH1 • LIAS • LIPT1 • MALAT1 • MFI2 • MTF1 • NPM1 • PDHA1 • SLC31A1

KLF4-mediated upregulation of the NKG2D ligand MICA in acute myeloid leukemia: a novel therapeutic target identified by enChIP. (PubMed, Cell Commun Signal) - "These data unravel a novel link between APTO253 and the innate anti-tumor immune response providing a rationale for targeting AML cells via APTO253-dependent KFL4/MICA induction to allow elimination by endogenous or transplanted NK and T cells in vivo. Video Abstract."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation • KLF4 • MICA • MYC • NKG2D

Aptose Reports Results for the Third Quarter 2022 (GlobeNewswire) - '“Tuspetinib' adopted as generic name for HM43239 – The United States Adopted Name (USAN) Council recently adopted 'tuspetinib' as the generic name for Aptose’s lead drug candidate HM43239, an oral, myeloid kinase inhibitor....Program costs for APTO-253 decreased by approximately $701 thousand, due to the Company’s decision on December 20, 2021 to discontinue further clinical development of APTO-253."

Discontinued • Pipeline update • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lung Cancer • Multiple Myeloma • Myelodysplastic Syndrome • Non Small Cell Lung Cancer • Oncology • Solid Tumor

A Phase 1a/b Dose Escalation Study of the MYC Repressor Apto-253 in Patients with Relapsed or Refractory AML or High-Risk MDS (ASH 2021) - P1 | "APTO-253 has been well-tolerated at doses of 20, 40, 66, 100 and 150 mg/m 2 over multiple cycles and escalated to 210 mg/m 2 (Cohort 6). PK analysis revealed that APTO-253 is rapidly transformed to and co-exists with the Fe(253) 3 in serum from R/R AML and high-risk MDS patients. Enrollment of patients at the 210 mg/m 2 dose level is ongoing and updated clinical data will be presented at the meeting."

Clinical • P1 data • Acute Myelogenous Leukemia • Fatigue • Myelodysplastic Syndrome • Oncology • MYC

A Study of APTO-253 in Patients With Relapsed or Refractory AML or MDS (clinicaltrials.gov) - P1; N=21; Terminated; Sponsor: Aptose Biosciences Inc.; N=60 ➔ 21; Trial completion date: May 2022 ➔ Sep 2021; Recruiting ➔ Terminated; Trial primary completion date: Feb 2022 ➔ Sep 2021; Drug manufacturing process and procedure review

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

"#Aptose reported its decision to discontinue further clinical development of #APTO253 $APTO https://t.co/9dsZ4nIXoQ" (@1stOncology)

Clinical

Aptose Provides Update on APTO-253 Program (GlobeNewswire) - "Aptose Biosciences Inc...announced its decision to discontinue further clinical development of APTO-253. The decision follows prioritization of the company’s other more advanced pipeline candidates, as well as an internal review of the product profile and performance to date of APTO-253, including a clinical hold placed by the U.S. Food & Drug Administration."

Discontinued • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

"$APTO Aptose Provides Update on APTO-253 Program https://t.co/k3mkXrGIEk" (@stock_titan)

Aptose Reports Results for the Third Quarter 2021 (GlobeNewswire) - "Development of New Formulation for Luxeptinib: The capsules have been GMP manufactured and passed stability tests; clinical studies are planned for 2022....Aptose has four abstracts, one for each of its ongoing clinical trials, accepted for presentation at the 63rd American Society of Hematology (ASH) Annual Meeting...Clinical data for HM43239 has been selected for an oral presentation. In addition, clinical data for luxeptinib and APTO-253 have been accepted for poster presentations."

Clinical data • New trial • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

KLF4 Promotes Diabetic Chronic Wound Healing by Suppressing Th17 Cell Differentiation in an MDSC-Dependent Manner. (PubMed, J Diabetes Res) - "MDSCs have been proven to mediate Th17 differentiation via cytokines, and our in vitro data showed that elevated KLF4 expression in MDSCs resulted in reduced Th17 cell numbers and, thus, decreased levels of cytokines indispensable for Th17 differentiation. Our study revealed a previously unreported function of KLF4-regulated MDSCs in diabetic wound healing and identified APTO-253 as a potential agent to improve the healing of pressure ulcers."

Journal • Myeloid-derived suppressor cells • Immunology • Inflammation • IL17A • KLF4

[VIRTUAL] A PHASE 1A/B DOSE ESCALATION STUDY OF THE MYC REPRESSOR APTO-253 IN PATIENTS WITH RELAPSED OR REFRACTORY AML OR HIGH-RISK MDS (EHA 2021) - P1 | "PK analysis revealed that APTO-253 is rapidly transformed to and co-exists with the Fe(253)3 in serum and their exposures resulted in suppression of MYC expression in whole blood samples from R/R AML and high-risk MDS patients. Enrollment of patients at the 150 mg/m2 dose level is ongoing and updated clinical data will be presented at the meeting."

Clinical • P1 data • Acute Myelogenous Leukemia • Fatigue • Infectious Disease • Myelodysplastic Syndrome • Oncology • Respiratory Diseases • MYC

[VIRTUAL] A Phase 1a/b Dose Escalation Study of the MYC Repressor Apto-253 in Patients with Relapsed or Refractory AML or High-Risk MDS (ASH 2020) - P1 | "APTO-253 has been well-tolerated in patients treated with 20, 40, 66, and 100 mg/m2 over multiple cycles. PK analysis revealed APTO-253 monomer rapidly transformed to and co-existed with the Fe(253)3 complex in peripheral blood and their exposures resulted in suppression of MYC expression in whole blood samples from R/R AML and high-risk MDS patients. Enrollment of patients at the 150 mg/m2 dose level is underway and updated clinical data will be presented at the meeting."

Clinical • P1 data • Acute Myelogenous Leukemia • Fatigue • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • FLT3 • MYC

Aptose Reports Results for the Second Quarter 2021 (GlobeNewswire) - "APTO-253 Phase 1 a/b Clinical Study in AML and MDS: Aptose currently is treating patients in the sixth dose cohort at 210 mg/m2 and several subsequent dose escalations are anticipated."

Trial status • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Multiple G-quadruplex binding ligand induced transcriptomic map of cancer cell lines. (PubMed, J Cell Commun Signal) - "Towards this, we assembled the transcripts differentially regulated by different G4DBLs and have also identified a core set of genes regulated in diverse cancer cell lines in response to 3 or more of these ligands. With the mode of action of G4DBLs towards topology shifts, folding, or disruption of G4 structure being currently visualized, we believe that this dataset will serve as a platform for assembly of G4DBL responsive transcriptome for comparative analysis of G4DBLs in multiple cancer cells based on the expression of specific cis-regulatory G4 associated genes in the future."

Journal • Preclinical • CNS Disorders • Oncology