The latest research results of GT19715, a new C-Myc/GSPT1 dual-target degrader of Pioneer Pharmaceutical, were published, which has good anti-acute myeloid leukemia and lymphoma efficacy

On October 13, 2022, Beijing time, Pioneer Pharmaceutical (stock code: 9939.
HK), a biopharmaceutical company focused on the development and industrialization of potential first-in-class and best-in-class innovative drugs, announces that its collaboration with The University of Texas MD Anderson Cancer Center has published its latest results in the journal Clinical Lymphoma, Myeloma & Leukemia on October 1, 2022.
The killing effect
of GT19715, a novel C-Myc/GSPT1 dual-target degrader developed by Pioneer Pharmaceutical, on acute myeloid leukemia (AML) and lymphoma was demonstrated.

C-Myc is an oncogenic transcription factor that plays a major role
in tumorigenesis, cancer cell survival, proliferation and immune escape.
c-Myc is an endogenous disorder protein (IPD) that lacks binding sites for small molecule inhibitors, so c-Myc is considered an "undruggable" target
.
Myc is highly expressed in AML that carries TP53 mutations or venetoclax (ven) resistance (Sallman, Blood 2021, nisida, ASH 2021).

However, targeting c-Myc or Myc pathway has not been successful and remains a major unmet clinical need
.

In recent years, targeted protein degradation is a hot area in the research and development of new drugs, which can be used to target previously undruggable targets, treat a variety of diseases by degrading disease-related proteins, and solve problems that traditional small molecules or biological macromolecules cannot solve
.
Small molecule targeted protein degradation drugs such as protein degradation targeted chimeras (PROTACs) or cerebron E3 ligase modulators (CELMoDs) are designed to target disease-relevant intracellular proteins by transferring them to the ubiquitin-proteasome system for degradation, targeting hitherto undruggable targets
.

Pioneer Pharmaceutical independently developed the c-Myc degrader GT19630 (GT19715 is the salt form of GT19630), and tested it in cell-free, cell-free experiments and animal experiments
.

The results showed that GT19630 effectively degraded c-Myc protein (IC50 = 1.
5 nM)
in HL-60 cells.
GT19630 binds to C-Myc in cell-free in vitro affinity experiments, and the proteasome inhibitor ixazomib completely blocks the degradation
of c-Myc by GT19630.
The IC50 of GT19715 in HL-60 cells was 1.
8 nM, which was significantly lower than the IC50 40.
2 nM of normal bone marrow cells in CFU testing, indicating a therapeutic window
。 In addition to its degradation of c-Myc, proteomic analysis showed that GT19630 also significantly degraded the GSPT1 (G1 to S phase transition proteins 1) protein that plays an important role in the survival of leukemia stem cells (LSC) (Surka et al.
Blood 2021
).

In fact, in xenograft animal models of HL-60 cells, GT19630 effectively degraded GSPT1 while completely degrading c-Myc and inhibiting tumor growth
at low doses of 0.
3 mg/kg/bid.
When GT19630 was dosed at 6 mg/kg, it had no effect
on normal myeloid cells in rats.
GT19715 clears circulatory lymphoma cells and prolongs survival in a c-Myc-driven model of systemic Daudi lymphoma
.
Importantly, GT19715 induced cell killing in a TP53-independent manner, but in MOLM-13 cells that had undergone CRISPR engineering knockout or TP53 mutations, GT19715 activity was significantly associated with c-Myc protein levels (R2 = 0.
86, P = 0.
02).

。 We found that MV4 compared to ven-sensitive parent cells; The 11 venetoclax-resistant (VR) cell line exhibits higher levels of c-Myc and GSPT1 proteins and shows greater sensitivity
to GT19715.
Finally, in the AML PDX model, GT19715 cleared human CD45+ AML cells
in mice compared to the control drug.

In summary, the preliminary experimental results of GT19715, a new c-Myc/GSPT1 degrader, show that it has good preclinical anti-lymphoma and leukemia efficacy, which provides a theoretical basis for
its clinical development.