Structure-Based Design of First-Generation Small Molecule Inhibitors Targeting the Catalytic Pockets of AID, APOBEC3A, and APOBEC3B.
Structure-Based Design of First-Generation Small Molecule Inhibitors Targeting the Catalytic Pockets of AID, APOBEC3A, and APOBEC3B.
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针对 AID、APOBEC3A 和 APOBEC3B 催化袋的第一代小分子抑制剂的基于结构的设计。
DOI：
10.1021/acsptsci.1c00091
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发表时间：
2021-08-13
影响因子：
--
通讯作者：
Larijani M
中科院分区：
文献类型：
--
作者：
King JJ;Borzooee F;Im J;Asgharpour M;Ghorbani A;Diamond CP;Fifield H;Berghuis L;Larijani M
激活诱导型胞苷脱氨酶(AID)通过突变B淋巴细胞中的免疫球蛋白基因来启动抗体多样化。AID和相关的APOBEC3(A3)酶也可以诱导全基因组的突变和损伤，这些突变和损伤与肿瘤的发生和发展有关。不同肿瘤基因组中最常见的突变特征归因于AID/A3s的错误突变活性。因此，抑制AID/A3s被认为是有治疗益处的。我们之前使用了一种计算生化的方法来洞察AID的催化口袋的结构，这导致了一种新型的调节AID/A3s的调节催化口袋的闭合，我们称之为“薛定谔催化口袋”。我们的发现随后得到了直接结构研究的证实。在这里，我们描述了我们寻找以AID的催化口袋为靶点的小分子。我们鉴定了抑制纯化的AID的小分子，细胞提取物中的AID，以及淋巴瘤细胞的内源性AID。类比扩展产生了效力更高的衍生品。这些化合物也被发现抑制A3A和A3B，这是AID的两个最具致瘤性的兄弟姐妹。两个化合物对AID和A3A的抑制微摩尔IC50较低，对A3A的抑制作用最强。对接表明，它们的弹头和AID、A3A和A3B的催化口袋内的残基之间，以及尾巴和催化口袋开口附近表面的DNA相互作用残基之间，存在着关键的相互作用。因此，这些残基的突变体降低了抑制效力。催化腔内和催化腔外的小分子和残基之间关键稳定相互作用的化学和丰富是治疗开发的希望。
Activation-induced cytidine deaminase (AID) initiates antibody diversification by mutating immunoglobulin loci in B lymphocytes. AID and related APOBEC3 (A3) enzymes also induce genome-wide mutations and lesions implicated in tumorigenesis and tumor progression. The most prevalent mutation signatures across diverse tumor genomes are attributable to the mistargeted mutagenic activities of AID/A3s. Thus, inhibiting AID/A3s has been suggested to be of therapeutic benefit. We previously used a computational-biochemical approach to gain insight into the structure of AID’s catalytic pocket, which resulted in the discovery of a novel type of regulatory catalytic pocket closure that regulates AID/A3s that we termed the “Schrodinger’s CATalytic pocket”. Our findings were subsequently confirmed by direct structural studies. Here, we describe our search for small molecules that target the catalytic pocket of AID. We identified small molecules that inhibit purified AID, AID in cell extracts, and endogenous AID of lymphoma cells. Analogue expansion yielded derivatives with improved potencies. These were found to also inhibit A3A and A3B, the two most tumorigenic siblings of AID. Two compounds exhibit low micromolar IC50 inhibition of AID and A3A, exhibiting the strongest potency for A3A. Docking suggests key interactions between their warheads and residues lining the catalytic pockets of AID, A3A, and A3B and between the tails and DNA-interacting residues on the surface proximal to the catalytic pocket opening. Accordingly, mutants of these residues decreased inhibition potency. The chemistry and abundance of key stabilizing interactions between the small molecules and residues within and immediately outside the catalytic pockets are promising for therapeutic development.
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影响因子：
16.6
作者：
通讯作者：
--
影响因子：
4.8
作者：
Branton，Sarah A.;Ghorbani，Atefeh;Larijani，Mani
通讯作者：
Larijani，Mani
影响因子：
30.8
作者：
Chan K;Roberts SA;Klimczak LJ;Sterling JF;Saini N;Malc EP;Kim J;Kwiatkowski DJ;Fargo DC;Mieczkowski PA;Getz G;Gordenin DA
通讯作者：
Gordenin DA
影响因子：
13.6
作者：
Di Giorgio, Salvatore;Martignano, Filippo;Conticello, Silvestro G.
通讯作者：
Conticello, Silvestro G.
DOI：
10.1016/j.bbagen.2019.129415
发表时间：
2019-11-01
影响因子：
3
作者：
Diamond, Cody P.;Im, Junbum;Larijani, Mani
通讯作者：
Larijani, Mani