1059 - Lisaftoclax (APG-2575) is a novel BCL-2 inhibitor with robust antitumor activity in preclinical models of hematologic malignancy

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Introduction: Unique challenges in drug design have largely constrained successful development of BCL-2-specific inhibitors because of BCL-2 homology domain 3– (BH3–) shared homology between BCL-2 family members and the shallow surface of their protein-protein interactions. This study reports discovery and extensive preclinical investigation of BCL-2 inhibitor lisaftoclax (APG-2575).

Methods: Lead compounds were developed using computational modeling, and the selectivity and potency of lisaftoclax were determined using biochemical binding, mitochondrial BH3 profiling, and cell-based viability or apoptosis assays. The antitumor effects of lisaftoclax were also assessed in several xenograft models.

Results: Lisaftoclax selectively bound BCL-2 (Ki < 0.1 nM), disrupted BCL-2:BIM complexes, and compromised mitochondrial outer membrane potential with BAX/BAK-dependent, caspase-mediated apoptosis. It also exerted strong antitumor activity in hematologic malignancy cell lines and tumor cells from patients with chronic lymphocytic leukemia, multiple myeloma, or Waldenström macroglobulinemia. Lisaftoclax treatment increased the expression of prodeath BCL-2 family proteins BIM and Noxa, and BIM translocated from the cytosol into the mitochondria. In line with these proapoptotic effects, lisaftoclax entered malignant cells rapidly, reached a plateau at 2 hours, and significantly downregulated mitochondrial respiratory function and production of ATP. Lisaftoclax also inhibited tumor growth in xenograft models, correlating with caspase activation and PARP-1 cleavage (a hallmark of apoptosis). Tumor growth inhibition by lisaftoclax furthermore corresponded with its pharmacokinetic profile, which included a short plasma elimination half-life (~6 hours), a longer half-life in tumors (13-48 hours), and a rapid attainment of maximum concentration to drive apoptosis. It has been suggested that BH3-mimetic BCL-2 inhibitors need to attain a mitochondrial threshold rapidly to trigger apoptosis, with their effects being driven by the rate of cell penetration and maximum concentration. In vivo, lisaftoclax combined with rituximab or bendamustine plus rituximab enhanced antitumor activity.

Conclusions: Lisaftoclax is a novel, orally bioavailable BH3 mimetic BCL-2-selective inhibitor with considerable potential in the treatment of certain hematologic malignancies. These preliminarily encouraging findings support ongoing clinical trials, including a phase 1, first-in-human study (Ailawadhi S et al. Clin Cancer Res 2023; In press: OF1-OF9. doi:10.1158/1078-0432.CCR-22-3321; NCT03537482) and phase 2 trial evaluating lisaftoclax alone or combined with Bruton tyrosine kinase inhibitors acalabrutinib or rituximab (Davids MS et al. Blood 2022; 140[suppl 1]:2326-2328. doi:10.1182/blood-2022-160386; NCT04215809).

Primary Author; Presenting Author(s)

AP

Aneel Paulus, MD

Assistant Professor of Medicine
Department of Cancer Biology and Division of Hematology and Oncology, Mayo Clinic
Jacksonville, FL, United States

Co-Author(s)

AM

Alak Manna, PhD

Department of Cancer Biology, Mayo Clinic
Jacksonville, FL, United States
HW

Hengbang Wang, PhD

Ascentage Pharma (Suzhou) Co., Ltd.
Suzhou, China (People's Republic)
JC

Jianyong Chen, PhD

Ascentage Pharma (Suzhou) Co., Ltd.
Suzhou, China (People's Republic)
PM

Ping Min, PhD

Ascentage Pharma (Suzhou) Co., Ltd.
Suzhou, China (People's Republic)
YY

Yan Yin, PhD

Ascentage Pharma (Suzhou) Co., Ltd.
Suzhou, China (People's Republic)
ND

Navnita Dutta, MS

Department of Cancer Biology, Mayo Clinic
Jacksonville, FL, United States
NH

Nabanita Halder, PhD

Department of Cancer Biology, Mayo Clinic
Jacksonville, FL, United States
GC

Gina Ciccio, BS

Department of Cancer Biology, Mayo Clinic
Jacksonville, FL, United States
JC

John A. Copland, III, PhD

Department of Cancer Biology, Mayo Clinic
Jacksonville, FL, United States
BH

Bing Han, MD, PhD

Department of Internal Medicine, Pharmacology and Medicinal Chemistry, Rogel Cancer Center, University of Michigan
Ann Arbor, MI, United States
LB

Longchuan Bai, PhD

Department of Internal Medicine, Pharmacology and Medicinal Chemistry, Rogel Cancer Center, University of Michigan
Ann Arbor, MI, United States
LL

Liu Liu, PhD

Department of Internal Medicine, Pharmacology and Medicinal Chemistry, Rogel Cancer Center, University of Michigan
Ann Arbor, MI, United States
MW

Mi Wang, PhD

Department of Internal Medicine, Pharmacology and Medicinal Chemistry, Rogel Cancer Center, University of Michigan
Ann Arbor, MI, United States
DM

Donna McEachern, N/A

Department of Internal Medicine, Pharmacology and Medicinal Chemistry, Rogel Cancer Center, University of Michigan
Ann Arbor, MI, United States
SP

Sally Przybranowski, MS

Department of Internal Medicine, Pharmacology and Medicinal Chemistry, Rogel Cancer Center, University of Michigan
Ann Arbor, MI, United States
CY

Chao-Yie Yang, PhD

Department of Internal Medicine, Pharmacology and Medicinal Chemistry, Rogel Cancer Center, University of Michigan
Ann Arbor, MI, United States
JS

Jeanne A. Stuckey, PhD

Department of Internal Medicine, Pharmacology and Medicinal Chemistry, Rogel Cancer Center, University of Michigan
Ann Arbor, MI, United States
DW

Depei Wu, MD

Department of Hematology, The First Affiliated Hospital of Soochow University
Suzhou, China (People's Republic)
CL

Caixia Li, MD

Department of Hematology, The First Affiliated Hospital of Soochow University
Suzhou, China (People's Republic)
Sikander Ailawadhi, MD

Professor of Medicine; Lead, International Cancer Center
Department of Cancer Biology, Mayo Clinic
Jacksonville, FL, United States
DY

Dajun Yang, MD, PhD

Ascentage Pharma (Suzhou) Co., Ltd., Ascentage Pharma Group Inc., and State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou
Suzhou, China (People's Republic)
SW

Shaomeng Wang, PhD

Department of Internal Medicine, Pharmacology and Medicinal Chemistry, Rogel Cancer Center, University of Michigan
Ann Arbor, MI, United States
AC

Asher A. Chanan-Khan, MBBS, MD

Department of Cancer Biology, Mayo Clinic and Mayo Clinic Cancer Center at St. Vincent’s Medical Center Riverside
Jacksonville, FL, United States
YZ

Yifan Zhai, MD, PhD

Ascentage Pharma Group Inc. and Ascentage Pharma (Suzhou) Co., Ltd.
Rockville, MD, United States