Journal: Cancers

Article Title: TP-0903 Is Active in Preclinical Models of Acute Myeloid Leukemia with TP53 Mutation/Deletion

doi: 10.3390/cancers15010029

Figure Lengend Snippet: TP-0903 inhibits aurora kinases in TP53 mutant AML cell lines. ( A ) MV4-11 (R248W) ( B ) HL-60 or ( C ) Kasumi-1 cells were treated with DMSO or increasing concentrations of TP-0903 for 4 h. Western blot analysis was performed on whole-cell lysates run on parallel gels with the indicated antibodies. Vinculin served as the loading control for each lysate. Immunoblots were quantified against respective loading controls using ImageJ. Data are representative of 3 independent experiments.

Article Snippet: Drugs were obtained from the following sources: TP-0903 tartrate (SPD Oncology, Cambridge, MA, USA), decitabine (LC-Labs, Woburn, MA, USA), and RG7388 (MedChemExpress, Monmouth Junction, NJ, USA).

Techniques: Mutagenesis, Western Blot, Control

Journal: Cancers

Article Title: TP-0903 Is Active in Preclinical Models of Acute Myeloid Leukemia with TP53 Mutation/Deletion

doi: 10.3390/cancers15010029

Figure Lengend Snippet: TP-0903 has in vitro activity in TP53 mutant AML cell lines. ( A ) MTT cell viability assay after MV4-11 (R248W), HL-60, and Kasumi-1 cell lines were treated with increasing concentrations of TP-0903 (n = 18 across three independent experiments). ( B ) Cell cycle analysis performed in MV4-11 (R248W), HL-60, and Kasumi-1 cell lines treated with 20 nM TP-0903 determined by flow cytometry using DAPI (n = 4–5). ( C ) Induction of apoptosis in MV4-11 (R248W), HL-60, and Kasumi-1 cell lines treated with TP-0903 (20 nM or 50 nM) for 24 h (black bar) or 48 h (grey bar) determined by flow cytometry using Annexin V (n = 3). Data represent the mean ± SEM. ( D ) MV4-11 (R248W), HL-60, and Kasumi-1 cell lines were plated with increasing concentrations of TP-0903 (10 nM, 50 nM) and counted on days 3 and 5. Cell counts/viability determined by trypan blue exclusion with Nexcelom Cellometer (n = 3). (* p < 0.05, ** p < 0.01, *** p <0.001, **** p <0.0001).

Article Snippet: Drugs were obtained from the following sources: TP-0903 tartrate (SPD Oncology, Cambridge, MA, USA), decitabine (LC-Labs, Woburn, MA, USA), and RG7388 (MedChemExpress, Monmouth Junction, NJ, USA).

Techniques: In Vitro, Activity Assay, Mutagenesis, Viability Assay, Cell Cycle Assay, Flow Cytometry

Journal: Cancers

Article Title: TP-0903 Is Active in Preclinical Models of Acute Myeloid Leukemia with TP53 Mutation/Deletion

doi: 10.3390/cancers15010029

Figure Lengend Snippet: TP-0903 induces DNA damage response in TP53 mutant AML cell lines. ( A ) MV4-11 (R248W), ( B ) HL-60, and ( C ) Kasumi-1 cells were treated with DMSO or TP-0903 at indicated concentrations for 4 h. Immunoblotting was performed to determine the expression of pChk1 (Ser345), pChk2 (Thr68), and pH2AX (Ser139/Tyr142). Vinculin served as the loading control for pChk1/Chk1 and pChk2/Chk2 blots. GAPDH served as the loading control for pH2AX/H2AX blots. Immunoblots were quantified against respective loading controls (vinculin or GAPDH) using ImageJ. Blots are representative of 2–3 independent experiments.

Article Snippet: Drugs were obtained from the following sources: TP-0903 tartrate (SPD Oncology, Cambridge, MA, USA), decitabine (LC-Labs, Woburn, MA, USA), and RG7388 (MedChemExpress, Monmouth Junction, NJ, USA).

Techniques: Mutagenesis, Western Blot, Expressing, Control

Journal: Cancers

Article Title: TP-0903 Is Active in Preclinical Models of Acute Myeloid Leukemia with TP53 Mutation/Deletion

doi: 10.3390/cancers15010029

Figure Lengend Snippet: Combinatorial in vitro activity of TP-0903 and decitabine. MTT cell viability assays were performed by treating ( A ) MV4-11 (R248W), ( B ) HL-60, and ( C ) Kasumi-1 cell lines with varying concentrations of TP-0903 and decitabine for 72 h (n = 18 across three independent experiments). Data were analyzed with surface-response using the highest single agent (HSA) model using Combenefit software.

Article Snippet: Drugs were obtained from the following sources: TP-0903 tartrate (SPD Oncology, Cambridge, MA, USA), decitabine (LC-Labs, Woburn, MA, USA), and RG7388 (MedChemExpress, Monmouth Junction, NJ, USA).

Techniques: In Vitro, Activity Assay, Software

Journal: Cancers

Article Title: TP-0903 Is Active in Preclinical Models of Acute Myeloid Leukemia with TP53 Mutation/Deletion

doi: 10.3390/cancers15010029

Figure Lengend Snippet: TP-0903 is active in an HL-60 xenograft model. Kaplan–Meier survival curve of NCG mice after intravenous injection with HL-60 cells (10 per treatment cohort). Fourteen days after TVI, mice were treated with vehicle, TP-0903 (50 mg/kg orally; 5 days on/2 days off), decitabine (0.4 mg/kg i.p.; 4 days on/10 days off), or the combination. Blue and red arrows represent days of TP-0903 and decitabine treatment, respectively. The TP-0903/decitabine combination prolonged median survival (75 days) compared to cohorts of mice treated with TP-0903 (63 days), decitabine (55 days), or vehicle (46 days) (**** p < 0.0001).

Article Snippet: Drugs were obtained from the following sources: TP-0903 tartrate (SPD Oncology, Cambridge, MA, USA), decitabine (LC-Labs, Woburn, MA, USA), and RG7388 (MedChemExpress, Monmouth Junction, NJ, USA).

Techniques: Injection

Journal: Cancers

Article Title: TP-0903 Is Active in Preclinical Models of Acute Myeloid Leukemia with TP53 Mutation/Deletion

doi: 10.3390/cancers15010029

Figure Lengend Snippet: TP-0903 is active in a MV4-11 (R248W)-Luc+ xenograft model. NSG mice were injected intravenously with MV4-11 (R248W) cells transfected with luciferase (MV4-11 (R248W)-Luc+) (5–6 per treatment cohort). Fourteen days after TVI, mice were treated with vehicle, TP-0903 (50 mg/kg orally; 5 days on/2 days off), decitabine (0.2 mg/kg i.p.; 4 days on/10 days off), or the combination for three cycles. Blue and red arrows represent days of TP-0903 and decitabine treatment, respectively. ( A ) Average radiance as determined by whole-body bioluminescence imaging performed weekly (left). Data represent the mean ± SEM. A two-way ANOVA demonstrated a significant difference between groups treated with TP-0903 or vehicle (* p < 0.05, ** p < 0.01). Representative whole-body bioluminescence images from day 41 (right). Each image uses the same scale. ( B ) Kaplan–Meier survival curve. Survival analysis demonstrated a significant survival advantage in mice treated with TP-0903 alone or the combination versus decitabine alone (** p < 0.01, *** p < 0.001, respectively) or vehicle (** p < 0.01, *** p < 0.001).

Article Snippet: Drugs were obtained from the following sources: TP-0903 tartrate (SPD Oncology, Cambridge, MA, USA), decitabine (LC-Labs, Woburn, MA, USA), and RG7388 (MedChemExpress, Monmouth Junction, NJ, USA).

Techniques: Injection, Transfection, Luciferase, Imaging

Journal: Current Oncology Reports

Article Title: Key Roles of AXL and MER Receptor Tyrosine Kinases in Resistance to Multiple Anticancer Therapies

doi: 10.1007/s11912-017-0579-4

Figure Lengend Snippet: AXL and MER inhibitors in preclinical and clinical development

Article Snippet: TP-0903 Tolero Pharmaceuticals , AXL , – , Preclinical.

Techniques:

Journal: Frontiers in Oncology

Article Title: Megakaryocytic Expansion in Gilteritinib-Treated Acute Myeloid Leukemia Patients Is Associated With AXL Inhibition

doi: 10.3389/fonc.2020.585151

Figure Lengend Snippet: Effect of Flt3-ITD on K562 response to inhibitors. (A) Schematic diagram of Flt3-ITD overexpressing cassettes. (B) Flow cytometric histogram showing gating strategy used for fluorescent-activated cell sorting. Sorted cells were analyzed several weeks after expansion and showed stably expressed Flt3. Neg, negative. (C) Western blot showing total Flt 3 protein expression from wild type, dim, and bright K562. Representative pictures from three independent experiment are shown. Bar graph showing mean±SD of Flt3 protein expression relative to GAPDH. * indicates significance compared with wild type. (D) Cell proliferation profile of wild type, dim, and bright K562 cultured under indicating conditions for 72 h. Bar graph showing mean±SD from three independent experiments performing in parallel. Flt3L, Flt3 ligand; IL3, interleukin 3. (E) Cell proliferation profile of wild type, dim, and bright K562 treated with indicating 4 nM gilteritinib, 8 nM quizartinib, and 100 nM dubermatinib for 72 h. Bar graph showing mean ± SD from three independent experiments performing in parallel.

Article Snippet: Gilteritinib, quizartinib, dubermatinib (TP-0903), and midostaurin were from Cayman chemical (Ann Arbor, MI, USA).

Techniques: FACS, Stable Transfection, Western Blot, Expressing, Cell Culture

Journal: Expert opinion on therapeutic targets

Article Title: Does Axl have potential as a therapeutic target in pancreatic cancer?

doi: 10.1080/14728222.2018.1527315

Figure Lengend Snippet: Clinical trials of therapies targeting Axl

Article Snippet: DDR1–2 1.5nM l/lb Advanced cancer MGCD516 NCT02219711 Mirati Therapeutics Inc. INCB081776 Axl/MerTK 0.61nM I Advanced solid tumors INCB081776 ± Nivolumab NCT03522142 Incyte Corporation Bemcentinib (BGB324) Axl, Tie-2, FLT4 14nM I and II Non-small cell lung cancer Bemcentinib + Erlotinib NCT02424617 BerGenBio ASA I and II Acute myeloid leukemia, myelodysplastic syndromes Bemcentinib ± Cytarabine or Decitabine NCT02488408 BerGenBio ASA II Lung cancer metastatic, NSCLC stage IV, Adenocarcinoma of lung Bemcentinib + Pembrolizumab NCT03184571 BerGenBio ASA II Triple negative breast cancer, inflammatory breast cancer stage IV Bemcentinib + Pembrolizumab NCT03184558 BerGenBio ASA TP-0903 Axl, MerTK, Tyro3, Aurora A/ B, JAK2, ALK.

Techniques: Clinical Proteomics, Modification