A lymphatic-absorbed multi-targeted kinase inhibitor for myelofibrosis therapy.
A lymphatic-absorbed multi-targeted kinase inhibitor for myelofibrosis therapy.
复制标题
DOI：
10.1038/s41467-022-32486-8
复制
发表时间：
2022-08-17
影响因子：
16.6
通讯作者：
Van Dort ME
中科院分区：
文献类型：
--
作者：
Ross BD;Jang Y;Welton A;Bonham CA;Palagama DSW;Heist K;Boppisetti J;Imaduwage KP;Robison T;King LR;Zhang EZ;Amirfazli C;Luker KE;Lee WY;Luker GD;Chenevert TL;Van Dort ME
癌症中代偿性信号传导节点的激活通常需要经常受到剂量限制性毒性困扰的联合治疗。肠淋巴药物吸收很少探索，虽然降低毒性和持续的药物水平将预期提高全身生物利用度。描述了一种有效的口服生物可利用的多功能激酶抑制剂（LP-182），其具有内在淋巴分配，用于组合靶向磷酸肌醇3-激酶（PI 3 K）和促分裂原活化蛋白激酶（MAPK）信号传导途径，而没有可观察到的毒性。我们通过减少下游激酶活化、改善疾病表型和提高骨髓纤维化动物模型的生存率来证明选择性和治疗效果。我们对小分子淋巴吸收的合成和理化性质的进一步表征将支持在淋巴向性治疗中的持续进步，以改变无数人类疾病适应症的疾病轨迹。同时抑制癌症中不同治疗靶标的联合疗法受到个体药代动力学特征的挑战。在这里，作者产生了一种口服提供的多靶点激酶抑制剂，该抑制剂在骨髓纤维化小鼠模型中被淋巴吸收并增加存活率。
Activation of compensatory signaling nodes in cancer often requires combination therapies that are frequently plagued by dose-limiting toxicities. Intestinal lymphatic drug absorption is seldom explored, although reduced toxicity and sustained drug levels would be anticipated to improve systemic bioavailability. A potent orally bioavailable multi-functional kinase inhibitor (LP-182) is described with intrinsic lymphatic partitioning for the combined targeting of phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways without observable toxicity. We demonstrate selectivity and therapeutic efficacy through reduction of downstream kinase activation, amelioration of disease phenotypes, and improved survival in animal models of myelofibrosis. Our further characterization of synthetic and physiochemical properties for small molecule lymphatic uptake will support continued advancements in lymphatropic therapy for altering disease trajectories of a myriad of human disease indications. Combination therapies simultaneously inhibiting different therapeutic targets in cancer is challenged by individual pharmacokinetic profiles. Here, the authors generate an orally provided multi-targeted kinase inhibitor that is lymphatic absorbed and increases survival in a murine model of myelofibrosis.
登录
查看更多内容
使用JAK和PAN级I PI3K抑制剂对骨髓增生性肿瘤的联合治疗。
影响因子：
5.3
作者：
Choong ML;Pecquet C;Pendharkar V;Diaconu CC;Yong JW;Tai SJ;Wang SF;Defour JP;Sangthongpitag K;Villeval JL;Vainchenker W;Constantinescu SN;Lee MA
通讯作者：
Lee MA
影响因子：
4.6
作者：
Dahan, A;Hoffman, A
通讯作者：
Hoffman, A
影响因子：
5.7
作者：
Guichard, Sylvie M.;Curwen, Jon;Cosulich, Sabina C.
通讯作者：
Cosulich, Sabina C.
影响因子：
2.9
作者：
Fischmann, Thierry O.;Smith, Catherine K.;Madison, Vincent S.
通讯作者：
Madison, Vincent S.
影响因子：
2.7
作者：
Brocks, Dion R.;Davies, Neal M.
通讯作者：
Davies, Neal M.