Abstract 5648: Effects of olverembatinib (HQP1351) in combination with BCL-2 inhibitor lisaftoclax (APG-2575) in T-cell acute lymphoblastic leukemia (T ALL)

Author: Zhai, Guoqing ; Min, Ping ; Yu, Huidan ; Yu, Zhou ; Zhai, Yifan ; Xiong, Yan ; Wu, Bingxing ; Yang, Dajun ; Liang, Zhiyan ; Peng, Bo

Background:T-ALL is a high-risk hematologic cancer arising from malignant transformation of T-cell progenitors, affecting approximately 15% of newly diagnosed pediatric and 25% of adult ALL cases. Survival in children, young adults, and patients with relapsed or refractory disease is poor with limited treatment options. Some T-ALL subtypes depend on pre-TCR/Src signaling and antiapoptotic BCL-2 family proteins for growth and survival. Olverembatinib, a novel multikinase inhibitor, targets oncogenic Src-family kinases (Lck, Fyn, and YES1) essential for T-cell differentiation, survival, and activation. Lisaftoclax is a novel BCL-2 inhibitor under investigation in late-stage clinical trials for multiple hematologic malignancies. Here, we examined the antitumor effects of olverembatinib combined with lisaftoclax in human T-ALL cell lines and explored potential mechanisms of action.Methods:Cellular proliferation was measured using CellTiter-Glo® assays and apoptosis by flow cytometry. Western blotting was used to elucidate potential mechanisms of action. In vivo activity was evaluated using a subcutaneous MOLT4 cell-derived xenograft mouse model.Results:Olverembatinib in combination with lisaftoclax exhibited strong synergistic antiproliferative effects in T-ALL cell lines MOLT4 and Jurkat, with combination indices of 0.2 and 0.1, respectively; apoptosis analyses revealed that the combination significantly increased the percentage of apoptotic cells compared to either agent alone (p < 0.0001). Olverembatinib 10 mg/kg or lisaftoclax 100 mg/kg alone resulted in no or limited tumor inhibition in MOLT4 xenograft model, with treatment-to-control (T/C) values of 113% and 89%, respectively. However, when co-administered, the combination enhanced tumor growth inhibition (T/C, 60%), achieving a synergy index of 1.67. Mechanistically, olverembatinib inhibited Lck activity, and when combined with lisaftoclax, synergistically reduced activity of downstream transcription factor NF-kB p65, leading to downregulation of the key antiapoptotic protein BCL-xL, which is typically upregulated in BCL-2 inhibitor-resistant T-ALL. In addition, the combination downregulated phosphorylation of AKT and GSK3b kinases, resulting in significant degradation of antiapoptotic protein MCL-1 and c-myc, an essential pro-survival oncogene in T-ALL. Increased cleavage of PARP and caspase-3 (markers of apoptosis) was also observed.Conclusions:Olverembatinib in combination with lisaftoclax demonstrated synergistic antitumor effects in T-ALL, providing a scientific rationale for further clinical evaluation of this novel combination therapy in patients with T-ALL.Citation Format:Bo Peng, Yan Xiong, Zhiyan Liang, Ping Min, Huidan Yu, Bingxing Wu, Guoqing Zhai, Zhou Yu, Dajun Yang, Yifan Zhai. Effects of olverembatinib (HQP1351) in combination with BCL-2 inhibitor lisaftoclax (APG-2575) in T-cell acute lymphoblastic leukemia (T-ALL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5648.

21 Apr 2025·Cancer Research

Abstract 1679: APG-2449, a novel focal adhesion kinase (FAK) inhibitor, enhances the antitumor activity of chemotherapy in preclinical models of small-cell lung cancer (SCLC) with activated FAK

Author: Liu, Daojie ; Yu, Zhou ; Zhai, Yifan ; Yang, Dajun ; Liang, Zhiyan ; Yao, Xinyi

AbstractBackground:SCLC is a genetically heterogeneous disease with no standardized targeted therapy options. Despite the recent advancement of immune checkpoint inhibitors, improvements in overall survival have been modest, and platinum-based chemotherapy combined with topoisomerase inhibitors remains the standard of care in SCLC. FAK, a non-receptor tyrosine kinase, has been reported to regulate cellular proliferation, migration, invasion, and DNA-damage repair. Previous studies have shown that FAK is amplified and overexpressed in SCLC tumors. Although non-small-cell lung cancer cells harboring FAK6, 7 (splicing isoforms of FAK that increase phosphorylation of FAK [pFAK]) are more sensitive to FAK inhibition than wild-type FAK (FAKWT), the expression and implications of FAK6, 7 expression in SCLC remain unclear. Given the role of FAK in cancer progression, we hypothesized that inhibition of FAK would augment the antitumor effects of chemotherapy in SCLC. The aim of this study was to evaluate the antitumor activity of investigational agent APG-2449 alone and combined with chemotherapy in SCLC.Methods:Cellular proliferation was measured by CellTiter-Glo® assays and apoptosis assessed via flow cytometry. Protein expression levels were examined via western blot. An H446 xenograft model was used to evaluate antitumor effects in vivo.Results:SCLC cell lines harboring FAK6, 7 (H446, H69, and H526) showed increased sensitivity to APG-2449 in a dose-dependent manner compared to a FAKWT cell line (DMS-114). When combined with chemotherapy (topotecan or etoposide plus carboplatin), APG-2449 synergistically decreased cell viability and increased apoptosis in H446 and H526 cell lines. Mechanistically, APG-2449 combined with topotecan and etoposide plus carboplatin enhanced DNA damage and apoptosis compared to either therapy alone in western blot assays. APG-2449 synergistically enhanced the antitumor effects of topotecan (synergy ratio: 22.08) and etoposide plus carboplatin (synergy ratio: 3.81) in the H446 xenograft model.Conclusions:Novel FAK inhibitor APG-2449 demonstrated a synergistic enhancement when combined with first- and second-line chemotherapies in SCLC, significantly increasing antitumor activity. These encouraging findings support further clinical development of APG-2449 for the treatment of patients with SCLC.Citation Format:Zhou Yu, Zhiyan Liang, Xinyi Yao, Daojie Liu, Dajun Yang, Yifan Zhai. APG-2449, a novel focal adhesion kinase (FAK) inhibitor, enhances the antitumor activity of chemotherapy in preclinical models of small-cell lung cancer (SCLC) with activated FAK [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1679.

21 Apr 2025·Cancer Research

Abstract 5651: Discovery of AS03157 as a highly potent and orally active antagonist of inhibitor of apoptosis proteins (IAPs)

Author: Han, Xiao ; Chen, Jianyong ; Liang, Zhiyan ; Hu, Jiantao ; Yu, Zhou ; Xiong, Yan ; Zhai, Yifan ; Yang, Dajun

AbstractBackground:Overexpression of antiapoptotic proteins, such as cellular inhibitor of apoptosis proteins 1 (cIAP1) and 2 (cIAP2) and X-linked IAP (XIAP), occurs in various hematologic and solid cancers and is associated with drug resistance and poor prognosis. Several small molecules are being investigated clinically as monotherapy or in combination therapy in solid tumors. AS03157, a novel and structurally distinct IAP antagonist, was identified with enhanced specificity towards cIAP1 and XIAP, and its pharmacological profiles were characterized in vitro and in vivo.Methods:Homogeneous time-resolved fluorescence assays were used to measure the binding of the compound to its target. Detroit 562 cell line was used to test the target degradation. MDA-MB-231 and EVSA-T breast cancer cell lines were used for antiproliferation assay. In vivo efficacy was evaluated in MDA-MB-231-derived xenograft model.Results:AS03157 strongly bound to cIAP1-BIR3 and XIAP-BIR3 at half-maximal inhibitory concentration (IC50) values of 4.3 nM and 13.7 nM, respectively. AS03157 inhibited cIAP1 with a half-maximal degradation concentration (DC50) of 1.38 nM after treatment for 2 hours in a Detroit 562 pharyngeal carcinoma cell line in vitro. AS03157 demonstrated potent growth inhibitory activities in MDA-MB-231 and EVSA-T breast cancer cell lines, with IC50 values of 20 nM and 2 nM, respectively. In addition, AS03157 exhibited high aqueous solubility, metabolic stability, as well as high oral bioavailability in both rodent and non-rodent species. Of interest, AS03157 10 and 20 mg/kg administered orally daily demonstrated dose-dependent antitumor activity in an MDA-MB-231-X1 human breast cancer xenograft model, with T/C values of 69.81% and 26.67% on Day 22, respectively.Conclusions:AS03157 showed promising in vitro and in vivo activity in preclinical cancer models, and these data provide a rationale for further clinical studies.Citation Format:Yan Xiong, Zhou Yu, Jiantao Hu, Jianyong Chen, Xiao Han, Zhiyan Liang, Yifan Zhai, Dajun Yang. Discovery of AS03157 as a highly potent and orally active antagonist of inhibitor of apoptosis proteins (IAPs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5651.

100 Deals associated with Suzhou Ascentage Pharma Co. Ltd.

100 Translational Medicine associated with Suzhou Ascentage Pharma Co. Ltd.

Corporation Tree

Boost your research with our corporation tree data.

view full example data

Pipeline

Pipeline Snapshot as of 20 May 2025

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

Preclinical

Current Projects

Drug(Targets)	Indications	Global Highest Phase

AS03157 ( IAP )	Neoplasms More	Preclinical
APG-5918 ( EED )	Prostatic Cancer More	Preclinical
APG-2449 ( ALK x FAK x ROS1 )	Acute Myeloid Leukemia More	Preclinical

Deal

Boost your decision using our deal data.

view full example data

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Profit

Explore the financial positions of over 360K organizations with Synapse.

view full example data

Grant & Funding(NIH)

Access more than 2 million grant and funding information to elevate your research journey.

view full example data

Investment

Gain insights on the latest company investments from start-ups to established corporations.

view full example data

Financing

Unearth financing trends to validate and advance investment opportunities.

view full example data

AI Agents Built for Biopharma Breakthroughs

Accelerate discovery. Empower decisions. Transform outcomes.

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis