Lisaftoclax (APG-2575)

Bcl-2 (IC50 = 2 nM); Bcl-xL (IC50 = 5.9 nM)

Lisaftoclax（化合物 6）在 Bcl-2 依赖性 RS4;11 细胞和 Bcl-xl 依赖性 Molm13 细胞中的 IC50 值分别为 5.5 nM 和 6.4 nM [1]。

lisaftoclax （APG-2575）和MDM2抑制剂alrizomadlin （APG-115）联合使用在体外对TP53野生型AML细胞系表现出协同抗增殖和凋亡活性。在AML细胞系来源和患者来源的异种移植模型中，这种协同作用进一步证明了深度抗肿瘤反应和延长生存期。有趣的是，通过慢性药物暴露或基因工程与临床相关的BCL-2基因突变建立的venetoclax耐药细胞和小鼠模型，联合治疗对（细胞凋亡）重新敏感。在体外用lisaftoclax和alrizomadlin治疗的venetoclax耐药AML患者的主要样本中，也证明了降低细胞活力和增殖的协同作用。机制上，alrizomadlin可能通过下调抗凋亡蛋白myeloid cell leukemia-1和BCL-extra-large的表达以及上调促死亡BCL-2相关的X蛋白，使癌细胞启动BCL-2抑制诱导的细胞凋亡。[2]

使用免疫检查点抑制剂（ICIs）的主要挑战是由于免疫抑制肿瘤微环境和缺乏足够的活化CD8+ T细胞浸润。将肿瘤微环境（TME）从“冷”转变为“热”，从而更有可能增强ICIs的作用，是一种很有前景的癌症治疗策略。我们发现选择性BCL-2抑制剂APG-2575可以增强抗pd -1治疗在同基因和人源化CD34+小鼠模型中的抗肿瘤效果。通过单细胞RNA测序，我们发现APG-2575将m2样免疫抑制巨噬细胞极化为m1样免疫刺激表型，增加CCL5和CXCL10的分泌，恢复t细胞功能并促进良好的免疫治疗反应。在机制上，我们证明了APG-2575直接结合NF-κB p65激活NLRP3信号，从而介导巨噬细胞再极化和促炎半胱天蛋白酶的激活，随后增加CCL5和CXCL10趋化因子的产生。由此可见，apg -2575诱导的巨噬细胞复极化可以重塑肿瘤免疫微环境，从而改善肿瘤免疫抑制，进一步增强抗肿瘤t细胞免疫。多重免疫组化证实免疫治疗效果较好的患者CD86、p-NF-κB p65、NLRP3水平较高，巨噬细胞CD206表达较低。总的来说，这些数据提供了证据，表明需要进一步研究APG-2575联合免疫疗法治疗肿瘤。[3]

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]

[1]. N-(PHENYLSULFONYL)BENZAMIDES AND RELATED COMPOUNDS AS BCL-2 INHIBITORS. Patent. WO2018027097A1.

[2]. Lisaftoclax in Combination with Alrizomadlin Overcomes Venetoclax Resistance in Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia: Preclinical Studies. Clin Cancer Res. 2023 Jan 4;29(1):183-196.

[3]. The BCL-2 inhibitor APG-2575 resets tumor-associated macrophages toward the M1 phenotype, promoting a favorable response to anti-PD-1 therapy via NLRP3 activation. Cell Mol Immunol. 2024 Jan;21(1):60-79.

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.

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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/

C45H48CLN7O8S

882.422728538513

881.297

C, 61.25; H, 5.48; Cl, 4.02; N, 11.11; O, 14.50; S, 3.63

2180923-05-9

137355972

Light yellow to yellow solid powder

7.5

192

3

12

12

62

1690

1

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

FNBXDBIYRAPDPI-BHVANESWSA-N

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

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

Bcl2/Bclxl inhibitor 1; APG2575; Bcl-2/Bcl-xl inhibitor 1; APG-2575; OSL3FEZ1IF; APG2575; UNII-OSL3FEZ1IF; LISAFTOCLAX [INN]; Lisaftoclax; APG-2575

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~113.32 mM)

配方 1 中的溶解度: 2.5 mg/mL (2.83 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 悬浮液；超声助溶。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。