用于依赖SLFN12的癌细胞杀伤的PDE3A调节剂的优化
Optimization of PDE3A Modulators for SLFN12-Dependent Cancer Cell Killing.
作者信息
Lewis Timothy A, de Waal Luc, Wu Xiaoyun, Youngsaye Willmen, Wengner Antje, Kopitz Charlotte, Lange Martin, Gradl Stefan, Ellermann Manuel, Lienau Philip, Schreiber Stuart L, Greulich Heidi, Meyerson Matthew
机构信息
Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States.
Dana-Farber Cancer Institute, Boston, Massachusetts 01255, United States.
出版信息
ACS Med Chem Lett. 2019 Oct 18;10(11):1537-1542. doi: 10.1021/acsmedchemlett.9b00360. eCollection 2019 Nov 14.
Abstract
6-(4-(Diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2)-one, or , potently and selectively inhibits phosphodiesterases 3A and 3B (PDE3A and PDE3B) and kills cancer cells by inducing PDE3A/B interactions with SFLN12. The structure-activity relationship (SAR) of analogs was evaluated using a phenotypic viability assay, resulting in several compounds with suitable pharmacokinetic properties for analysis. One of these compounds, , was active in an SK-MEL-3 xenograft model of cancer.
摘要
6-(4-(二乙氨基)-3-硝基苯基)-5-甲基-4,5-二氢哒嗪-3(2)-酮，即 ，可有效且选择性地抑制磷酸二酯酶3A和3B（PDE3A和PDE3B），并通过诱导PDE3A/B与SFLN12相互作用来杀死癌细胞。使用表型活力测定法评估了 类似物的构效关系（SAR），得到了几种具有适合 分析的药代动力学性质的化合物。其中一种化合物， 在SK-MEL-3癌症异种移植模型中具有活性。
相似文献
1
Optimization of PDE3A Modulators for SLFN12-Dependent Cancer Cell Killing.用于依赖SLFN12的癌细胞杀伤的PDE3A调节剂的优化
ACS Med Chem Lett. 2019 Oct 18;10(11):1537-1542. doi: 10.1021/acsmedchemlett.9b00360. eCollection 2019 Nov 14.
2
Mechanistic insights into cancer cell killing through interaction of phosphodiesterase 3A and schlafen family member 12.通过磷酸二酯酶 3A 和 Schlafen 家族成员 12 的相互作用了解癌细胞杀伤的机制。
J Biol Chem. 2020 Mar 13;295(11):3431-3446. doi: 10.1074/jbc.RA119.011191. Epub 2020 Jan 31.
3
Identification of cancer-cytotoxic modulators of PDE3A by predictive chemogenomics.通过预测性化学基因组学鉴定PDE3A的癌症细胞毒性调节剂。
Nat Chem Biol. 2016 Feb;12(2):102-8. doi: 10.1038/nchembio.1984. Epub 2015 Dec 14.
4
Phosphodiesterase 3A: a new player in development of interstitial cells of Cajal and a prospective target in gastrointestinal stromal tumors (GIST).磷酸二酯酶3A：在 Cajal 间质细胞发育中的新角色及胃肠道间质瘤（GIST）的潜在靶点。
Oncotarget. 2017 Jun 20;8(25):41026-41043. doi: 10.18632/oncotarget.17010.
5
Multiple PDE3A modulators act as molecular glues promoting PDE3A-SLFN12 interaction and induce SLFN12 dephosphorylation and cell death.多种 PDE3A 调节剂作为分子胶促进 PDE3A-SLFN12 相互作用，并诱导 SLFN12 去磷酸化和细胞死亡。
Cell Chem Biol. 2022 Jun 16;29(6):958-969.e5. doi: 10.1016/j.chembiol.2022.01.006. Epub 2022 Jan 31.
6
Discovery of BAY 2666605, a Molecular Glue for PDE3A and SLFN12.BAY 2666605的发现，一种PDE3A和SLFN12的分子胶。
ACS Med Chem Lett. 2024 Sep 10;15(10):1662-1667. doi: 10.1021/acsmedchemlett.4c00336. eCollection 2024 Oct 10.
7
Structure of PDE3A-SLFN12 complex and structure-based design for a potent apoptosis inducer of tumor cells.PDE3A-SLFN12 复合物结构及基于结构的肿瘤细胞强效凋亡诱导剂设计。
Nat Commun. 2021 Oct 27;12(1):6204. doi: 10.1038/s41467-021-26546-8.
8
Structure of PDE3A-SLFN12 complex reveals requirements for activation of SLFN12 RNase.PDE3A-SLFN12 复合物结构揭示了 SLFN12 核糖核酸酶激活的要求。
Nat Commun. 2021 Jul 16;12(1):4375. doi: 10.1038/s41467-021-24495-w.
9
SFPQ, a multifunctional nuclear protein, regulates the transcription of .SFPQ是一种多功能核蛋白，可调节……的转录。 （原文此处不完整）
Biosci Rep. 2017 Aug 31;37(4). doi: 10.1042/BSR20170975. Epub 2017 Jul 25.
10
PDE3A inhibitor anagrelide activates death signaling pathway genes and synergizes with cell death-inducing cytokines to selectively inhibit cancer cell growth.磷酸二酯酶3A抑制剂阿那格雷激活死亡信号通路基因，并与诱导细胞死亡的细胞因子协同作用，以选择性抑制癌细胞生长。
Am J Cancer Res. 2019 Sep 1;9(9):1905-1921. eCollection 2019.
引用本文的文献
1
Pharmacokinetic profile and anticancer efficacy of anagrelide administered subcutaneously in rodents.皮下注射阿那格雷在啮齿动物体内的药代动力学特征及抗癌疗效。
Drug Deliv. 2025 Dec;32(1):2463433. doi: 10.1080/10717544.2025.2463433. Epub 2025 Feb 10.
2
First-in-Human Dose-Escalation Study of the First-in-Class PDE3A-SLFN12 Complex Inducer BAY 2666605 in Patients with Advanced Solid Tumors Coexpressing SLFN12 and PDE3A.一流的PDE3A-SLFN12复合物诱导剂BAY 2666605在共表达SLFN12和PDE3A的晚期实体瘤患者中的首次人体剂量递增研究。
Clin Cancer Res. 2024 Dec 16;30(24):5568-5576. doi: 10.1158/1078-0432.CCR-24-2713.
3
Discovery of BAY 2666605, a Molecular Glue for PDE3A and SLFN12.BAY 2666605的发现，一种PDE3A和SLFN12的分子胶。
ACS Med Chem Lett. 2024 Sep 10;15(10):1662-1667. doi: 10.1021/acsmedchemlett.4c00336. eCollection 2024 Oct 10.
4
Velcrin molecular glues induce apoptosis in glioblastomas with high and expression.Velcrin分子胶水可诱导高[具体基因名称缺失]表达的胶质母细胞瘤发生凋亡。
Neurooncol Adv. 2024 Jul 1;6(1):vdae115. doi: 10.1093/noajnl/vdae115. eCollection 2024 Jan-Dec.
5
Enhancing Urological Cancer Treatment: Leveraging Vasodilator Synergistic Potential with 5-FU for Improved Therapeutic Outcomes.增强泌尿系统癌症治疗效果：利用血管舒张剂与5-氟尿嘧啶的协同潜力以改善治疗结果。
J Clin Med. 2024 Jul 14;13(14):4113. doi: 10.3390/jcm13144113.
6
A PDE3A-SLFN12 Molecular Glue Exhibits Significant Antitumor Activity in TKI-Resistant Gastrointestinal Stromal Tumors.PDE3A-SLFN12 分子胶在 TKI 耐药胃肠间质瘤中显示出显著的抗肿瘤活性。
Clin Cancer Res. 2024 Aug 15;30(16):3603-3621. doi: 10.1158/1078-0432.CCR-24-0096.
7
Is a Highly Expressed Therapy Target in Myxoid Liposarcoma.是黏液样脂肪肉瘤中高表达的治疗靶点。
Cancers (Basel). 2023 Nov 7;15(22):5308. doi: 10.3390/cancers15225308.
8
Understanding the Clinical Use of Levosimendan and Perspectives on its Future in Oncology.了解左西孟旦的临床应用及其在肿瘤学领域的未来前景。
Biomolecules. 2023 Aug 24;13(9):1296. doi: 10.3390/biom13091296.
9
Schlafen 12 restricts HIV-1 latency reversal by a codon-usage dependent post-transcriptional block in CD4+ T cells.睡眠 12 通过 CD4+T 细胞中依赖于密码子使用的转录后阻断限制 HIV-1 潜伏期逆转。
Commun Biol. 2023 May 10;6(1):487. doi: 10.1038/s42003-023-04841-y.
10
Anagrelide: A Clinically Effective cAMP Phosphodiesterase 3A Inhibitor with Molecular Glue Properties.阿那格雷：一种具有分子胶特性的临床有效环磷酸腺苷磷酸二酯酶3A抑制剂。
ACS Med Chem Lett. 2023 Mar 28;14(4):350-361. doi: 10.1021/acsmedchemlett.3c00092. eCollection 2023 Apr 13.
本文引用的文献
1
Estrogen-Related Hormones Induce Apoptosis by Stabilizing Schlafen-12 Protein Turnover.雌激素相关激素通过稳定 Schlafen-12 蛋白周转诱导细胞凋亡。
Mol Cell. 2019 Sep 19;75(6):1103-1116.e9. doi: 10.1016/j.molcel.2019.06.040. Epub 2019 Aug 13.
2
Targeting tumor cells based on Phosphodiesterase 3A expression.基于磷酸二酯酶3A表达靶向肿瘤细胞。
Exp Cell Res. 2017 Dec 15;361(2):308-315. doi: 10.1016/j.yexcr.2017.10.032. Epub 2017 Oct 26.
3
Phosphodiesterase 3A: a new player in development of interstitial cells of Cajal and a prospective target in gastrointestinal stromal tumors (GIST).磷酸二酯酶3A：在 Cajal 间质细胞发育中的新角色及胃肠道间质瘤（GIST）的潜在靶点。
Oncotarget. 2017 Jun 20;8(25):41026-41043. doi: 10.18632/oncotarget.17010.
4
Identification of cancer-cytotoxic modulators of PDE3A by predictive chemogenomics.通过预测性化学基因组学鉴定PDE3A的癌症细胞毒性调节剂。
Nat Chem Biol. 2016 Feb;12(2):102-8. doi: 10.1038/nchembio.1984. Epub 2015 Dec 14.
5
Expression and regulation of Schlafen (SLFN) family members in primary human monocytes, monocyte-derived dendritic cells and T cells.Schlafen（SLFN）家族成员在原代人单核细胞、单核细胞衍生的树突状细胞和T细胞中的表达与调控。
Results Immunol. 2015 Oct 22;5:23-32. doi: 10.1016/j.rinim.2015.10.001. eCollection 2015.
6
Phosphodiesterase inhibitors. Part 4: design, synthesis and structure-activity relationships of dual PDE3/4-inhibitory fused bicyclic heteroaromatic-4,4-dimethylpyrazolones.磷酸二酯酶抑制剂。第 4 部分：双重 PDE3/4 抑制性融合双环杂芳基-4,4-二甲基吡唑酮的设计、合成和构效关系。
Bioorg Med Chem Lett. 2012 Sep 15;22(18):5833-8. doi: 10.1016/j.bmcl.2012.07.088. Epub 2012 Jul 31.
7
Copper-catalyzed direct amination of ortho-functionalized haloarenes with sodium azide as the amino source.铜催化邻位官能化卤代芳烃与叠氮化钠的直接胺化反应。
J Org Chem. 2010 May 21;75(10):3311-6. doi: 10.1021/jo100345t.
8
Defining the binding site of levosimendan and its analogues in a regulatory cardiac troponin C-troponin I complex.确定左西孟旦及其类似物在调节性心肌肌钙蛋白C-肌钙蛋白I复合物中的结合位点。
Biochemistry. 2008 Jul 15;47(28):7485-95. doi: 10.1021/bi800438k. Epub 2008 Jun 21.
9
The effects of levosimendan and OR-1896 on isolated hearts, myocyte-sized preparations and phosphodiesterase enzymes of the guinea pig.左西孟旦和OR-1896对豚鼠离体心脏、心肌细胞大小的标本及磷酸二酯酶的影响。
Eur J Pharmacol. 2004 Feb 13;486(1):67-74. doi: 10.1016/j.ejphar.2003.12.005.
10
Oxazolidinone structure-activity relationships leading to linezolid.导致利奈唑胺的恶唑烷酮结构-活性关系。
Angew Chem Int Ed Engl. 2003 May 9;42(18):2010-23. doi: 10.1002/anie.200200528.
Zotero 插件