GT19715 / Kintor Pharma - LARVOL DELTA

MYC/GSPT1 protein degradation in refractory/relapsed T-cell prolymphocytic leukemias (ASH 2025) - "T-PLLs are one of the most challenging hematologic malignancies based onrefractoriness to conventional chemotherapy and targeted therapies, including alemtuzumab.Chromosome rearrangement and overexpression of TCL-1 are hallmarks of T-PLL, accounting forapproximately 95% of cases...We investigated the activity of GT19715 in T-PLL patient-derivedxenograft (PDX) models established from relapsed/refractory T-PLL patients in vitro and in vivo... We identified increased protein translation of c-Myc and GSPT1 in T-PLL cells compared tonormal PBMCs. Targeted protein degradation of c-Myc and GSPT1 is highly effective inrelapsed/refractory T-PLL in vitro and in vivo, with over 900% extension of survival in a clinically relevant,PDX T-PLL model, providing rationale for clinical investigations."

IO biomarker • Hematological Malignancies • Leukemia • Lymphoma • Prolymphocytic Leukemia • Targeted Protein Degradation • BCL2 • CD2 • CD69 • CD7 • DPP4 • GSPT1 • MCL1 • MYC • STAT5 • STAT5AWqe • ZAP70

Overcoming midostaurin resistance via dual MYC and GSPT1 degradation by the protac GT19715 in FLT3-amplified AML cells (ASH 2025) - "To counteract this, the c-Myc/GSPT1 degrader GT19715 inducedsynergistic cell death in midostaurin-resistant MR cells by suppressing FLT3 expression through GSPT1degradation-mediated SCR. Meanwhile, AKT escape from FLT3 regulation in MR cells under drug selectionpressure may contribute to the development of FLT3-independent resistance."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Targeted Protein Degradation • ATF4 • CASP3 • FLT3 • GSPT1 • MYC • STAT5

Protein degradation of MYC/GSPT1 combined with menin inhibition overcomes resistance to menin inhibition in KMT2A-rearranged Acute Myeloid Leukemia (ASH 2025) - "Pharmacological inhibition of the menin-KMT2A interaction using revumenib andziftomenib has shown encouraging efficacy in clinical trials, and revumenib has been FDA-approved(Aldoss & Issa, 2023)...By targeting the MYC-GSPT1 axis, GT19715, the first-in-class MYC/GSPT1degrader, has shown promising activity in c-MYC-driven hematological malignancies through disruptionof MYC/GSPT1 protein translation (Nishida, biorxiv 650490, in revision)... The proposed combinatorial approach of menin inhibition and MYC/GSPT1 proteindegradation induces highly synergistic cell death in KMT2A-r AML cells in vitro and in vivo, effectivelyovercoming resistance by MCL-1 overexpression and RAS pathway activation. Investigations usingKMT2Ar AML patient-derived xenograft models are ongoing and will be presented."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Targeted Protein Degradation • ANXA5 • GSPT1 • KMT2A • MCL1 • MYC • NRAS

Protein degradation of MYC/GSPT1 is a novel treatment modality for aggressive T-cell acute lymphoblastic leukemias (ASH 2025) - "Indeed, ABT-263, a BCL-2/BCL-XL inhibitor, incombination with GT19715 induced synergistic cell death. MYC/GSPT1 protein degradation is highly active in T-ALL cells in vitro, with substantial reduction of MYCand GSPT1, leading to disruption of nascent protein synthesis. GT19715 profoundly extended survival ofmice carrying PDX T-ALL cells by 680%. Persistent T-ALL cells showed sustained BCL-XL levels andcombinatorial inhibition of BCL-XL with MYC/GSPT1 protein degradation synergistically induced celldeath."

IO biomarker • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • T Acute Lymphoblastic Leukemia • Targeted Protein Degradation • T-cell Acute Lymphoblastic Lymphoma • ANXA5 • BCL2 • BCL2L1 • CD1a • CD2 • CD33 • CD34 • CD5 • CD7 • CD8 • GSPT1 • HOXA9 • NOTCH1 • PTPRC

Targeting Co-Regulatory Feedback Loop of MYC and GSPT1 By MYC/GSPT1 Dual Degradation Is Synthetic Lethal in Combination with Ven/Aza in TP53 Mutant Acute Myeloid Leukemia Stem and Progenitor Cells (ASH 2024) - "ASH 2022, 2023), induced significantly greater GFP signals than CC-90009, a selective GSPT1 CELMoD, suggesting that dual MYC/GSPT1 degradation enhances SCR on MYC gene...Quiescent LSPCs exhibit sensitivity particularly to Venetoclax (Ven) (Zeng et al...Indeed, the combinatorial treatment of GT19715 with Ven/5'-azacitidine (Aza) exhibited synergistic cell kill (Bliss index 67.67, P = 2.11e-10) in CD34+CD38- LSCs in primary TP53 mutant AML samples (N = 7)...The combinatorial treatment nearly eradicated these remaining AML cells in bone marrow samples in another ongoing PDX AML experiment (PDX824) carrying TP53 p.Y220C and p.G105fs, suggesting that the combinatorial approach of dual MYC/GSPT1 degradation with Ven/Aza can be an effective therapeutic approach for TP53 mutant AML. Conclusion : we identified a novel positive co-regulatory feedback loop between MYC and GSPT1, and found that dual MYC/GSPT1 degradation by GT19715 profoundly synergized in the induction of cell..."

Combination therapy • IO biomarker • Synthetic lethality • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • ATF3 • ATF4 • BCL2 • CD34 • CRBN • GSPT1 • GYPA • MYC • TFRC • TP53

Stem-Cell Enriched Cellular Hierarchy of TP53 Mutant Acute Myeloid Leukemia Is Vulnerable to Targeted Protein Degradation of c-MYC (ASH 2023) - "GT19715 but did not reduce total mouse BM CD45+ cells, suggesting favorable toxicity profiles of GT19715. In conclusion, TP53mut AML comprised highly enriched LSC populations compared to TP53wt AML and targeting of c-MYC protein is highly effective in TP53mut AML in vitro and in vivo with a therapeutic window between AML LSC and normal hematopoietic cells."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • CD34 • CRBN • MECOM • MYC • NRAS • PTPRC

Targeted Protein Degradation for c-MYC Overcomes Therapy Resistance in T-Cell Acute Lymphoblastic Leukemias (ASH 2023) - "GT19715 also enhanced cell death induced by dexamethasone. Targeted protein degradation of c-MYC induces promising anti-leukemia efficacy in T-ALL cells in vitro and in vivo. Further mechanistic and in vivo studies are ongoing."

IO biomarker • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • T Acute Lymphoblastic Leukemia • Targeted Protein Degradation • T-cell Acute Lymphoblastic Lymphoma • BCL2 • BRD4 • CD1a • CD33 • CD34 • CD5 • CD7 • CD8 • CRBN • FBXW7 • KRAS • MYC • NOTCH1 • PTEN • PTPRC • TP53

TARGETING MUTANT TP53 ACUTE MYELOID LEUKEMIA THROUGH DISRUPTION OF MYC-GSPT1 AXIS (EHA 2025) - "GT19715 induced significantly greater SCR signals than CC-90009, a selective GSPT1 degrader, suggesting that dual MYC/GSPT1 degradation enhances SCR of MYC...Quiescent LSPCs exhibit sensitivity particularly to Venetoclax (Ven) (Zeng et al...GT19715 with Ven/5'-azacitidine (Aza) exhibited synergistic cell kill (Bliss index 67.67, P = 2.11e-10) in CD34+CD38- primary TP53 mutant AML LSCs (N = 7)... We identified a novel role of MYC in controlling translation termination and discovered that dual MYC/GSPT1 degradation by GT19715 profoundly synergized with Ven/Aza in TP53 mutant quiescent and proliferating AML stem/progenitor cells, resulting in substantial survival prolongation in TP53 mutant AML PDX models."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • ATF3 • ATF4 • BCL2 • CD34 • GSPT1 • GYPA • MYC • TFRC • TP53

KMT2A rearranged acute myeloid leukemia is vulnerable to the combinatorial inhibition of menin and MYC protein degradation (AACR 2025) - "This interaction has been targeted by menin inhibitors revunemib and ziftomenib with promising results in clinical trials (Aldoss & Issa, 2023; Erba, 2022), and revumenib is now FDA-approved...We have investigated GT19715, the first-in-class MYC/GSPT1 degrader in MYC-driven hematological malignancies (Nishida, ASH 2022, 2023, 2024)... Combinatorial approach of menin inhibition and MYC degradation results in a profound synergistic reduction of KMT2Ar AML cells in vitro and in vivo, validating the underlying premise. Further mechanistic studies and efficacy in PDX models are ongoing."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • GSPT1 • KMT2A • MYC • TP53

TARGETING MYC BY DEGRADATION REWIRES METABOLOMICS AND INDUCES CELL KILL IN TP53 MUTANT ACUTE MYELOID LEUKEMIAS (EHA 2024) - "To directly target c-MYC protein, weemployed GT19715 (GT715), the first-in-class cereblon modulator for c-MYC in TP53mut AML in vitro and invivo...To better target LSC and improve theefficacy of GT715, we combined GT715 with venetoclax and 5'-azacitidine, and induced synergistic cell death inprimary TP53mut AML samples... Single-cell based approaches identified increased MYC levels in the enriched leukemiastem/progenitor fractions, especially in LPs and MEPs. Targeting c-MYC by GT715 induced promising anti-leukemia efficacy in vitro and in vivo. GT715 was well tolerated in humanized Crbn mice, warranting clinicaldevelopment for the devastating disease."

IO biomarker • Acute Myelogenous Leukemia • Anemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • CD34 • CRBN • FBXW7 • MYC • NRAS • TFRC

C-MYC Targeting By Degradation: Novel Dual c-Myc/GSPT1 Degrader GT19715 Induces TP53-Independent Cell Death in Acute Myeloid Leukemia and Lymphomas (ASH 2022) - "MYC is highly expressed in Burkitt's leukemia/lymphomas and also in TP53 mutant and venetoclax (ven) resistant AML (Sallman, Blood 2021, Nishida, ASH 2021)...A proteasome inhibitor ixazomib completely blocked c-Myc degradation, confirming CRL4CRBN-dependent c-Myc degradation as mechanism...A) and exerted a 20x higher cytoreductive potency compared to CC-90009 (IC50 of 1.8 nM vs 40.4 nM for GT19715 and CC-90009, respectively) in HL-60 cells... The novel dual c-Myc/GSPT1 degrader GT19715 exerts TP53 independent preclinical anti-lymphoma and -leukemia efficacy, providing rationale for its clinical development."

Acute Myelogenous Leukemia • Burkitt Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Oncology • Targeted Protein Degradation • ANXA5 • CD34 • GSPT1 • MYC • PTPRC • TP53

Kintor Pharma Announces Oral Presentation at ASH 2022 Highlighting the Data from Novel Dual c-Myc/GSPT1 Degrader GT19715 (PRNewswire) - "Kintor Pharmaceutical Limited...announced that the results from the novel dual c-Myc/GSPT1 degrader GT19715 have been selected for oral presentation at the annual meeting of the American Society of Hematology 2022 (ASH 2022), and the abstract is available on ASH's official website....GT19715 demonstrated promising anti-leukemia efficacy in patient-derived AML cells with TP53 mutations, especially in immature CD34+ fractions; and treatment of GT19715 in mice eradicated lymphoma and leukemia cells in Daudi Burkitt's lymphoma and Venetoclax-resistant AML models."

Preclinical • Acute Myelogenous Leukemia • Burkitt Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology