Targeting Bruton tyrosine kinase using non-covalent inhibitors in B cell malignancies.
Targeting Bruton tyrosine kinase using non-covalent inhibitors in B cell malignancies.
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DOI：
10.1186/s13045-021-01049-7
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发表时间：
2021-03-06
影响因子：
28.5
通讯作者：
Miao Y
中科院分区：
文献类型：
--
作者：
Gu D;Tang H;Wu J;Li J;Miao Y
B 细胞受体 (BCR) 信号传导参与 B 细胞恶性肿瘤的发病机制。 BCR 信号传导的激活可促进恶性 B 细胞的存活和增殖。布鲁顿酪氨酸激酶 (BTK) 是 BCR 信号传导的关键组成部分，使 BTK 成为重要的治疗靶点。几种共价BTK抑制剂在治疗B细胞恶性肿瘤，特别是慢性淋巴细胞白血病方面显示出显着的疗效。然而，对共价 BTK 抑制剂的获得性耐药在 B 细胞恶性肿瘤中并不罕见。获得性耐药的一个主要机制是 BTK 半胱氨酸 481 (C481) 突变的出现，该突变会破坏共价 BTK 抑制剂的结合。此外，由于共价抑制剂对除 BTK 之外的激酶的脱靶抑制而导致的不良事件也很常见。如果发生获得性耐药或无法耐受的不良事件，则需要替代治疗方案。非共价 BTK 抑制剂不与 C481 结合，因此为 B 细胞恶性肿瘤患者（包括那些对共价 BTK 抑制剂产生耐药性的患者）提供了潜在有效的选择。初步临床研究表明非共价 BTK 抑制剂有效且耐受性良好。在这篇综述中，我们讨论了使用非共价 BTK 抑制剂的基本原理以及非共价 BTK 抑制剂在 B 细胞恶性肿瘤中的临床前和临床研究。
B cell receptor (BCR) signaling is involved in the pathogenesis of B cell malignancies. Activation of BCR signaling promotes the survival and proliferation of malignant B cells. Bruton tyrosine kinase (BTK) is a key component of BCR signaling, establishing BTK as an important therapeutic target. Several covalent BTK inhibitors have shown remarkable efficacy in the treatment of B cell malignancies, especially chronic lymphocytic leukemia. However, acquired resistance to covalent BTK inhibitors is not rare in B cell malignancies. A major mechanism for the acquired resistance is the emergence of BTK cysteine 481 (C481) mutations, which disrupt the binding of covalent BTK inhibitors. Additionally, adverse events due to the off-target inhibition of kinases other than BTK by covalent inhibitors are common. Alternative therapeutic options are needed if acquired resistance or intolerable adverse events occur. Non-covalent BTK inhibitors do not bind to C481, therefore providing a potentially effective option to patients with B cell malignancies, including those who have developed resistance to covalent BTK inhibitors. Preliminary clinical studies have suggested that non-covalent BTK inhibitors are effective and well-tolerated. In this review, we discussed the rationale for the use of non-covalent BTK inhibitors and the preclinical and clinical studies of non-covalent BTK inhibitors in B cell malignancies.
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影响因子：
24.7
作者：
Davids, Matthew S.;Brander, Danielle M.;Brown, Jennifer R.
通讯作者：
Brown, Jennifer R.
慢性淋巴细胞白血病患者对 BTK 抑制产生耐药性的克隆进化
影响因子：
16.6
作者：
Burger JA;Landau DA;Taylor-Weiner A;Bozic I;Zhang H;Sarosiek K;Wang L;Stewart C;Fan J;Hoellenriegel J;Sivina M;Dubuc AM;Fraser C;Han Y;Li S;Livak KJ;Zou L;Wan Y;Konoplev S;Sougnez C;Brown JR;Abruzzo LV;Carter SL;Keating MJ;Davids MS;Wierda WG;Cibulskis K;Zenz T;Werner L;Dal Cin P;Kharchencko P;Neuberg D;Kantarjian H;Lander E;Gabriel S;O'Brien S;Letai A;Weitz DA;Nowak MA;Getz G;Wu CJ
通讯作者：
Wu CJ
影响因子：
3.1
作者：
Chen, Jun;Kinoshita, Taisei;Chang, Betty Y.
通讯作者：
Chang, Betty Y.
影响因子：
28.5
作者：
Elgamal, Ola A.;Mehmood, Abeera;Byrd, John C.
通讯作者：
Byrd, John C.
影响因子：
7.5
作者：
Epperla, Narendranath;Shana'ah, Arwa Y.;Woyach, Jennifer A.
通讯作者：
Woyach, Jennifer A.