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Structure-Based Design and Identification of FT-2102 (Olutasidenib), a Potent Mutant-Selective IDH1 Inhibitor.
Journal of Medicinal Chemistry ( IF 7.3 ) Pub Date : 2020-02-12 , DOI: 10.1021/acs.jmedchem.9b01423 Justin A Caravella 1 , Jian Lin 1 , R Bruce Diebold 1 , Ann-Marie Campbell 2 , Anna Ericsson 1 , Gary Gustafson 2 , Zhongguo Wang 1 , Jennifer Castro 1 , Andrea Clarke 1 , Deepali Gotur 1 , Helen R Josephine 1 , Marie Katz 1 , Mark Kershaw 2 , Lili Yao 2 , Angela V Toms 1 , Kenneth J Barr 1 , Christopher J Dinsmore 1 , Duncan Walker 1 , Susan Ashwell 1 , Wei Lu 1
Journal of Medicinal Chemistry ( IF 7.3 ) Pub Date : 2020-02-12 , DOI: 10.1021/acs.jmedchem.9b01423 Justin A Caravella 1 , Jian Lin 1 , R Bruce Diebold 1 , Ann-Marie Campbell 2 , Anna Ericsson 1 , Gary Gustafson 2 , Zhongguo Wang 1 , Jennifer Castro 1 , Andrea Clarke 1 , Deepali Gotur 1 , Helen R Josephine 1 , Marie Katz 1 , Mark Kershaw 2 , Lili Yao 2 , Angela V Toms 1 , Kenneth J Barr 1 , Christopher J Dinsmore 1 , Duncan Walker 1 , Susan Ashwell 1 , Wei Lu 1
Affiliation
Inhibition of mutant IDH1 is being evaluated clinically as a treatment option for oncology. Here we describe the structure-based design and optimization of quinoline lead compounds to identify FT-2102, a potent, orally bioavailable, brain penetrant, and selective mIDH1 inhibitor. FT-2102 has excellent ADME/PK properties and reduces 2-hydroxyglutarate levels in an mIDH1 xenograft tumor model. This compound has been selected as a candidate for clinical development in hematologic malignancies, solid tumors, and gliomas with mIDH1.
中文翻译:
FT-2102(Olutasidenib)(一种有效的突变体选择性IDH1抑制剂)的基于结构的设计和鉴定。
突变IDH1的抑制作用正在临床上作为肿瘤学的治疗选择进行评估。在这里,我们描述了基于喹啉化合物的结构设计和优化,以鉴定FT-2102,FT-2102是一种有效的,口服生物利用的,脑渗透剂和选择性mIDH1抑制剂。FT-2102具有出色的ADME / PK特性,并降低了mIDH1异种移植肿瘤模型中的2-羟基戊二酸水平。该化合物已被选为具有mIDH1的血液系统恶性肿瘤,实体瘤和神经胶质瘤临床开发的候选药物。
更新日期:2020-02-12
中文翻译:
FT-2102(Olutasidenib)(一种有效的突变体选择性IDH1抑制剂)的基于结构的设计和鉴定。
突变IDH1的抑制作用正在临床上作为肿瘤学的治疗选择进行评估。在这里,我们描述了基于喹啉化合物的结构设计和优化,以鉴定FT-2102,FT-2102是一种有效的,口服生物利用的,脑渗透剂和选择性mIDH1抑制剂。FT-2102具有出色的ADME / PK特性,并降低了mIDH1异种移植肿瘤模型中的2-羟基戊二酸水平。该化合物已被选为具有mIDH1的血液系统恶性肿瘤,实体瘤和神经胶质瘤临床开发的候选药物。