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Lisaftoclax (Bcl-2/Bcl-xl inhibitor 1; APG2575) is a novel and potent dual inhibitor of Bcl-2 and Bcl-xl with anticancer activity. It inhibits Bcl-2 and Bcl-xl with IC50 of 2 nM and 5.9 nM, respectively.
On July 10, 2025, Ascentage Pharma announced that its proprietary novel Bcl-2 selective inhibitor lisaftoclax (APG-2575) has been approved by China’s National Medical Products Administration (NMPA) for the treatment of adult patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who have previously received at least one systemic therapy including Bruton’s tyrosine kinase (BTK) inhibitors, which makes lisaftoclax the first Bcl-2 inhibitor receiving conditional approval and marketing authorization for the treatment of patients with CLL/SLL in China, and the second Bcl-2 inhibitor approved globally.| Targets |
Bcl-2 (IC50 = 2 nM); Bcl-xL (IC50 = 5.9 nM)
Lisaftoclax (APG-2575) is a selective BCL-2 inhibitor (IC50 = 1-100 nM for BCL-2). It shows >500-fold selectivity over BCL-xL (IC50 >1 μM) and minimal activity against MCL-1. [1][2] |
|---|---|
| ln Vitro |
Lisaftoclax (10–1000 nM) induced dose-dependent apoptosis in venetoclax-resistant AML cell lines (MOLM-13/Ven-R, IC50 = 42 nM), with 80% Annexin V+ cells at 100 nM after 48h. Western blot showed cleavage of caspase-9 and PARP. [2]
In co-culture systems, Lisaftoclax (200 nM) reprogrammed M2 macrophages to M1 phenotype, increasing IL-1β secretion by 8-fold (p<0.001) and TNF-α by 6-fold (p<0.01) via NLRP3 inflammasome activation. [3] Lisaftoclax (compound 6) IC50 values in Bcl-2-dependent RS4;11 cells and Bcl-xl-dependent Molm13 cells are 5.5 nM and 6.4 nM, respectively [1]. |
| ln Vivo |
The combination of lisaftoclax (APG-2575) and MDM2 inhibitor alrizomadlin (APG-115) exhibited synergistic antiproliferative and apoptogenic activities in TP53 wild-type AML cell lines in vitro. This synergy was further exemplified by deep antitumor responses and prolonged survival in AML cell line-derived and patient-derived xenograft models. Interestingly, the combination treatment resensitized (to apoptosis) venetoclax-resistant cellular and mouse models established via chronic drug exposure or genetically engineered with clinically relevant BCL-2 gene mutations. Synergistic effects in reducing cellular viability and proliferation were also demonstrated in primary samples of patients with venetoclax-resistant AML treated with lisaftoclax and alrizomadlin ex vivo. Mechanistically, alrizomadlin likely primes cancer cells to BCL-2 inhibition-induced cellular apoptosis by downregulating expression of antiapoptotic proteins myeloid cell leukemia-1 and BCL-extra-large and upregulating pro-death BCL-2-associated X protein.[2]
In venetoclax-resistant AML PDX models, Lisaftoclax (100 mg/kg p.o. QD) reduced tumor burden by 78% (p<0.001) after 28 days. Combination with alrizomadlin achieved complete regression in 5/8 mice. [2] In MC38 syngeneic models, Lisaftoclax (150 mg/kg p.o.) increased tumor-infiltrating CD8+ T cells by 3.2-fold (p<0.01) and synergized with anti-PD-1 (tumor volume reduction: 92% vs. 45% monotherapy). [3] |
| Cell Assay |
Apoptosis assay: Cells treated with Lisaftoclax (0.1–10 μM) for 24–72h were stained with Annexin V/PI. Flow cytometry quantified apoptosis rates. [2]
Immunoblotting: Treated cells lysed for BCL-2 family protein analysis (Bax, Bak, cleaved caspase-9). β-actin used as loading control. [2] Cytokine profiling: ELISA measured IL-1β, TNF-α, and IL-10 in macrophage supernatants after 24h treatment. [3] The main challenges in the use of immune checkpoint inhibitors (ICIs) are ascribed to the immunosuppressive tumor microenvironment and the lack of sufficient infiltration of activated CD8+ T cells. Transforming the tumor microenvironment (TME) from "cold" to "hot" and thus more likely to potentiate the effects of ICIs is a promising strategy for cancer treatment. We found that the selective BCL-2 inhibitor APG-2575 can enhance the antitumor efficacy of anti-PD-1 therapy in syngeneic and humanized CD34+ mouse models. Using single-cell RNA sequencing, we found that APG-2575 polarized M2-like immunosuppressive macrophages toward the M1-like immunostimulatory phenotype with increased CCL5 and CXCL10 secretion, restoring T-cell function and promoting a favorable immunotherapy response. Mechanistically, we demonstrated that APG-2575 directly binds to NF-κB p65 to activate NLRP3 signaling, thereby mediating macrophage repolarization and the activation of proinflammatory caspases and subsequently increasing CCL5 and CXCL10 chemokine production. As a result, APG-2575-induced macrophage repolarization could remodel the tumor immune microenvironment, thus improving tumor immunosuppression and further enhancing antitumor T-cell immunity. Multiplex immunohistochemistry confirmed that patients with better immunotherapeutic efficacy had higher CD86, p-NF-κB p65 and NLRP3 levels, accompanied by lower CD206 expression on macrophages. Collectively, these data provide evidence that further study on APG-2575 in combination with immunotherapy for tumor treatment is required.[3] |
| Animal Protocol |
Venetoclax-sensitive and venetoclax-resistant acute myeloid leukemia (AML) and acute lymphoblastic leukemia cells and xenograft models were used to evaluate antitumor effects and underlying mechanisms associated with combined BCL-2 inhibitor lisaftoclax (APG-2575) and MDM2 inhibitor alrizomadlin (APG-115).[2]
For PDX studies: NSG mice received Lisaftoclax (100 mg/kg) or vehicle (30% PEG400/5% solutol) orally daily. Alrizomadlin (10 mg/kg) was administered IV twice weekly. [2] For immunotherapy studies: C57BL/6 mice bearing MC38 tumors received Lisaftoclax (150 mg/kg in 0.5% methylcellulose) QD + anti-PD-1 (200 μg IP) every 3 days. [3] |
| ADME/Pharmacokinetics |
Oral bioavailability in mice: 65%. Plasma t1/2 = 4.3 h. Steady-state concentrations (Cmin) >200 nM at 100 mg/kg QD. [2]
Plasma protein binding: 93% across species. [2] |
| Toxicity/Toxicokinetics |
No significant body weight loss or hematological toxicity at therapeutic doses. Platelet counts maintained >150×109/L. [2]
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| References | |
| Additional Infomation |
Lisaftoclax is a novel, orally active, selective and potent BCL-2 inhibitor
Lisaftoclax is an orally bioavailable and selective inhibitor of the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2), with potential pro-apoptotic and antineoplastic activities. Upon oral administration, lisaftoclax targets, binds to and inhibits the activity of Bcl-2. This restores apoptotic processes in tumor cells. Bcl-2 is overexpressed in many cancers and plays an important role in the negative regulation of apoptosis; its expression is associated with increased drug resistance and tumor cell survival. Purpose: This global phase I trial investigated the safety, efficacy, pharmacokinetics, and pharmacodynamics of lisaftoclax (APG-2575), a novel, orally active, potent selective B-cell lymphoma 2 (BCL-2) inhibitor, in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (R/R CLL/SLL) and other hematologic malignancies (HMs). Patients and methods: Maximum tolerated dose (MTD) and recommended phase II dose were evaluated. Outcome measures were safety and tolerability (primary) and pharmacokinetic variables and antitumor effects (secondary). Pharmacodynamics in patient tumor cells were explored. Results: Among 52 patients receiving lisaftoclax, MTD was not reached. Treatment-emergent adverse events (TEAEs) included diarrhea (48.1%), fatigue (34.6%), nausea (30.8%), anemia and thrombocytopenia (28.8% each), neutropenia (26.9%), constipation (25.0%), vomiting (23.1%), headache (21.2%), peripheral edema and hypokalemia (17.3% each), and arthralgia (15.4%). Grade ≥ 3 hematologic TEAEs included neutropenia (21.2%), thrombocytopenia (13.5%), and anemia (9.6%), none resulting in treatment discontinuation. Clinical pharmacokinetic and pharmacodynamic results demonstrated that lisaftoclax had a limited plasma residence and systemic exposure and elicited rapid clearance of malignant cells. With a median treatment of 15 (range, 6-43) cycles, 14 of 22 efficacy-evaluable patients with R/R CLL/SLL experienced partial responses, for an objective response rate of 63.6% and median time to response of 2 (range, 2-8) cycles. Conclusions: Lisaftoclax was well tolerated, with no evidence of tumor lysis syndrome. Dose-limiting toxicity was not reached at the highest dose level. Lisaftoclax has a unique pharmacokinetic profile compatible with a potentially more convenient daily (vs. weekly) dose ramp-up schedule and induced rapid clinical responses in patients with CLL/SLL, warranting continued clinical investigation.Clin Cancer Res . 2023 Jul 5;29(13):2385-2393. https://pubmed.ncbi.nlm.nih.gov/37074726/ Lisaftoclax overcomes venetoclax resistance by disrupting BCL-2/MCL-1 heterodimerization and activating Bax-dependent apoptosis. [2] Phase Ib/II clinical trials ongoing for hematologic malignancies (NCT03537482, NCT04771546). [3] |
| Molecular Formula |
C45H48CLN7O8S
|
|---|---|
| Molecular Weight |
882.422728538513
|
| Exact Mass |
881.297
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| Elemental Analysis |
C, 61.25; H, 5.48; Cl, 4.02; N, 11.11; O, 14.50; S, 3.63
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| CAS # |
2180923-05-9
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| PubChem CID |
137355972
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
7.5
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| Hydrogen Bond Donor Count |
3
|
| Hydrogen Bond Acceptor Count |
12
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| Rotatable Bond Count |
12
|
| Heavy Atom Count |
62
|
| Complexity |
1690
|
| Defined Atom Stereocenter Count |
1
|
| SMILES |
ClC1C=CC(=CC=1)C1=C(CN2CCN(C3C=CC(C(NS(C4C=CC(=C(C=4)[N+](=O)[O-])NC[C@H]4COCCO4)(=O)=O)=O)=C(C=3)OC3C=NC4=C(C=CN4)C=3)CC2)CCC2(C1)CCC2
|
| InChi Key |
FNBXDBIYRAPDPI-BHVANESWSA-N
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| InChi Code |
InChI=1S/C45H48ClN7O8S/c46-33-4-2-30(3-5-33)39-25-45(12-1-13-45)14-10-32(39)28-51-16-18-52(19-17-51)34-6-8-38(42(23-34)61-35-22-31-11-15-47-43(31)49-26-35)44(54)50-62(57,58)37-7-9-40(41(24-37)53(55)56)48-27-36-29-59-20-21-60-36/h2-9,11,15,22-24,26,36,48H,1,10,12-14,16-21,25,27-29H2,(H,47,49)(H,50,54)/t36-/m0/s1
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| Chemical Name |
4-[4-[[8-(4-chlorophenyl)spiro[3.5]non-7-en-7-yl]methyl]piperazin-1-yl]-N-[4-[[(2S)-1,4-dioxan-2-yl]methylamino]-3-nitrophenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
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| Synonyms |
Bcl2/Bclxl inhibitor 1; APG2575; APG-2575; OSL3FEZ1IF; UNII-OSL3FEZ1IF; LISAFTOCLAX [INN]; LISAFTOCLAX [WHO-DD]; 4-(4-((6-(4-CHLOROPHENYL)SPIRO(3.5)NON-6-EN-7-YL)METHYL)-PIPERAZIN-1-YL)-N-((3-NITRO-4-(((2S)-1,4-DIOXAN-2-YLMETHYL)AMINO)PHENYL)SULFONYL)-2-(1HPYRROLO(2,3-B)PYRIDIN-5-YLOXY)BENZAMIDE; ...; 2180923-05-9; Bcl-2/Bcl-xl inhibitor 1; OSL3FEZ1IF; APG 2575; UNII-OSL3FEZ1IF; LISAFTOCLAX [INN]; Lisaftoclax; APG-2575
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~113.32 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (2.83 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.1332 mL | 5.6662 mL | 11.3325 mL | |
| 5 mM | 0.2266 mL | 1.1332 mL | 2.2665 mL | |
| 10 mM | 0.1133 mL | 0.5666 mL | 1.1332 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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