Ascentage Pharma, a global biopharmaceutical company specializing in hematological malignancies, has presented encouraging preclinical data for five investigational oncology drug candidates at the American Association of Cancer Research (AACR) 2025 annual meeting in Chicago. The studies highlight the company's innovative pipeline targeting key apoptosis regulators and oncogenic pathways.
Olverembatinib and Lisaftoclax Combination Shows Promise in Leukemia
Two of the most promising presentations focused on the combination of novel tyrosine kinase inhibitor olverembatinib (HQP1351) with Bcl-2 inhibitor lisaftoclax (APG-2575) in different leukemia models.
In acute myeloid leukemia (AML), the combination demonstrated significant activity in overcoming venetoclax resistance—a major clinical challenge for elderly patients or those ineligible for intensive chemotherapy. Venetoclax combined with hypomethylating agents is currently the standard of care for these patients, but resistance often develops.
Olverembatinib targets multiple kinases associated with leukemogenesis and venetoclax resistance in AML, including FLT3, cKIT, PDGFR, Src family kinases, PI3K, and FGFR. When combined with lisaftoclax, the duo synergistically inhibited cellular proliferation and induced apoptosis in venetoclax-resistant AML cell lines.
The same combination also showed promise in T-cell acute lymphoblastic leukemia (T-ALL), a high-risk hematologic cancer affecting approximately 15% of newly diagnosed pediatric and 25% of adult ALL cases. Survival rates for relapsed or refractory T-ALL remain poor, with limited treatment options.
Olverembatinib targets oncogenic Src-family kinases essential for T-cell differentiation, survival, and activation. The combination with lisaftoclax synergistically suppressed tumor growth in a MOLT4 xenograft model, suggesting a potential new approach for this difficult-to-treat malignancy.
APG-5918 Shows Synergy with Enzalutamide in Prostate Cancer
Another promising candidate, APG-5918, an embryonic ectoderm development protein (EED) inhibitor, demonstrated potent anti-tumor activity in prostate cancer models. Castration-resistant prostate cancer (CRPC) remains incurable due to resistance to therapies including androgen receptor pathway inhibitors like enzalutamide.
Dysregulation of polycomb repressive complex 2 (PRC2) is common in prostate cancer and associated with poor prognosis and metastasis. APG-5918 alone showed superior inhibitory effects on prostate cancer cell proliferation in vitro, while its combination with enzalutamide synergistically suppressed cell proliferation.
The combination induced deeper G0/G1 cell cycle arrest than either agent alone and enhanced downregulation of oncogenic drivers and DNA methylation factors, suggesting a potential strategy to overcome resistance in advanced prostate cancer.
APG-2449 Enhances Chemotherapy in Small-Cell Lung Cancer
APG-2449, a novel focal adhesion kinase (FAK) inhibitor, demonstrated enhanced anti-tumor activity when combined with chemotherapy in small-cell lung cancer (SCLC) models with activated FAK.
SCLC is a genetically heterogeneous disease with limited targeted therapy options. Despite recent advances in immunotherapy, improvements in overall survival have been modest, with platinum-based chemotherapy combined with topoisomerase inhibitors remaining the standard of care.
FAK, a non-receptor tyrosine kinase that regulates cellular proliferation, migration, invasion, and DNA-damage repair, is amplified and overexpressed in approximately 69% of SCLC tumors. APG-2449 showed synergistic anti-tumor effects when combined with both first- and second-line chemotherapies in SCLC models, potentially offering a new approach for this aggressive malignancy.
AS03157: A Novel IAP Antagonist
The fifth presentation introduced AS03157, a highly potent and orally active antagonist of inhibitor of apoptosis proteins (IAPs). Overexpression of antiapoptotic proteins such as cellular inhibitor of apoptosis protein 1 (cIAP1), cIAP2, and X-linked IAP (XIAP) occurs in various hematologic and solid cancers and is associated with drug resistance and poor prognosis.
AS03157, a structurally distinct IAP antagonist, demonstrated enhanced specificity toward cIAP1 and XIAP, binding with high affinity and efficiently targeting cIAP1 for degradation. This resulted in potent antiproliferative activities (with IC50 values below 30 nM) in tested cancer cell lines, positioning it as a promising candidate for further clinical development.
Company Perspective and Status
Dr. Yifan Zhai, Chief Medical Officer at Ascentage, commented on the findings: "The encouraging data from our investigational assets is another testament to our strong and innovative pipeline. In particular, the combination of olverembatinib and lisaftoclax, two of our key drug candidates, has demonstrated strong synergistic effects in preclinical models of acute myeloid leukemia and T-cell acute lymphoblastic leukemia."
Ascentage Pharma has been listed on the Hong Kong Stock Exchange since October 2019 and recently joined the Nasdaq Global Market in January 2025. The company has the distinction of being the only organization in the world with active clinical programs targeting all known key apoptosis regulators.
Olverembatinib is already approved in China, with all approved indications included in the China National Reimbursement Drug List. Meanwhile, lisaftoclax has received Priority Review designation from China's Center for Drug Evaluation.
All five drug candidates presented at AACR 2025—olverembatinib, lisaftoclax, APG-2449, APG-5918, and AS03157—remain investigational in the United States and have not yet received FDA approval.
