Phenotypic screening identifies a trisubstituted imidazo[1,2-a]pyridine series that induces differentiation in multiple AML cell lines.
Phenotypic screening identifies a trisubstituted imidazo[1,2-a]pyridine series that induces differentiation in multiple AML cell lines.
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表型筛选鉴定出可诱导多种 AML 细胞系分化的三取代咪唑并[1,2-a]吡啶系列。
DOI：
10.1016/j.ejmech.2023.115509
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发表时间：
2023
影响因子：
6.7
通讯作者：
Josa-Culleré L
中科院分区：
文献类型：
--
作者：
Josa-Culleré L
急性髓性白血病（AML）是一种侵袭性白血病，长期生存率低。虽然目前的治疗标准是基于细胞毒性化疗，一个有前途的新兴方法是分化治疗。然而，目前大多数分化剂靶向特定的突变，并且仅在某些患者亚型中有效。为了鉴定可能在更广泛人群中有效的药物，我们用骨髓标志物CD11b进行了表型筛选，并鉴定了一系列化合物，这些化合物能够在体外分化AML细胞系，而不管它们的突变状态如何。构效关系研究表明，用磺酰胺和吲唑分别取代甲酰胺和邻苯二酚甲醚基团可改善该系列化合物的体外代谢特征，同时保持其在多种细胞系中的分化特征。这种优化操作使得先导化合物能够进行体内功效测试。我们的工作支持表型筛选的承诺，以确定新的小分子诱导分化的广泛的AML亚型。
Acute myeloid leukaemia (AML) is an aggressive type of leukaemia with low rates of long-term survival. While the current standard of care is based on cytotoxic chemotherapy, a promising emerging approach is differentiation therapy. However, most current differentiating agents target specific mutations and are effective only in certain patient subtypes. To identify agents which may be effective in wider population cohorts, we performed a phenotypic screen with the myeloid marker CD11b and identified a compound series that was able to differentiate AML cell linesin vitroregardless of their mutation status. Structure-activity relationship studies revealed that replacing the formamide and catechol methyl ether groups with sulfonamide and indazole respectively improved thein vitrometabolic profile of the series while maintaining the differentiation profile in multiple cell lines. This optimisation exercise enabled progression of a lead compound toin vivoefficacy testing. Our work supports the promise of phenotypic screening to identify novel small molecules that induce differentiation in a wide range of AML subtypes.
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影响因子：
20.3
作者：
Stein, Eytan M.;Garcia-Manero, Guillermo;Tallman, Martin S.
通讯作者：
Tallman, Martin S.
DOI：
10.1056/nejmoa1301689
发表时间：
2013-05-30
期刊：
The New England journal of medicine
影响因子：
--
作者：
Cancer Genome Atlas Research Network;Ley TJ;Miller C;Ding L;Raphael BJ;Mungall AJ;Robertson A;Hoadley K;Triche TJ Jr;Laird PW;Baty JD;Fulton LL;Fulton R;Heath SE;Kalicki-Veizer J;Kandoth C;Klco JM;Koboldt DC;Kanchi KL;Kulkarni S;Lamprecht TL;Larson DE;Lin L;Lu C;McLellan MD;McMichael JF;Payton J;Schmidt H;Spencer DH;Tomasson MH;Wallis JW;Wartman LD;Watson MA;Welch J;Wendl MC;Ally A;Balasundaram M;Birol I;Butterfield Y;Chiu R;Chu A;Chuah E;Chun HJ;Corbett R;Dhalla N;Guin R;He A;Hirst C;Hirst M;Holt RA;Jones S;Karsan A;Lee D;Li HI;Marra MA;Mayo M;Moore RA;Mungall K;Parker J;Pleasance E;Plettner P;Schein J;Stoll D;Swanson L;Tam A;Thiessen N;Varhol R;Wye N;Zhao Y;Gabriel S;Getz G;Sougnez C;Zou L;Leiserson MD;Vandin F;Wu HT;Applebaum F;Baylin SB;Akbani R;Broom BM;Chen K;Motter TC;Nguyen K;Weinstein JN;Zhang N;Ferguson ML;Adams C;Black A;Bowen J;Gastier-Foster J;Grossman T;Lichtenberg T;Wise L;Davidsen T;Demchok JA;Shaw KR;Sheth M;Sofia HJ;Yang L;Downing JR;Eley G
通讯作者：
Eley G
影响因子：
20.3
作者：
Levis, Mark;Ravandi, Farhad;Smith, B. Douglas
通讯作者：
Smith, B. Douglas
影响因子：
11.5
作者：
Dhillon, Sohita
通讯作者：
Dhillon, Sohita
影响因子：
20.3
作者：
Sexauer, Amy;Perl, Alexander;Levis, Mark
通讯作者：
Levis, Mark