Tarloxotinib bromide (TH-4000)

Tarloxotinib bromide is an irreversible EGFR/HER2 inhibitor.

To confirm the mechanism of action, Tarloxotinib bromide is shown to be metabolized efficiently under hypoxia using a panel of human NSCLC cell lines (rate of TKI release 0.4-2.1 nM/hr/106 cells), a process that is inhibited by oxygen (TKI release 80% (538 vs 99 nM/kg; p

A prototypic WT EGFR driven xenograft model (A431) is used to benchmark Tarloxotinib bromide activity against each EGFR-TKI by 'retrotranslation' of reported plasma exposure for each agent in human subjects back to the xenograft model. Only treatment with clinically relevant doses and schedules of Tarloxotinib bromide is associated with tumor regression and durable inhibition of WT EGFR tumor phosphorylation. Consistent with these findings, Tarloxotinib bromide treatment can also regress the WT EGFR NSCLC tumor models H125 and H1648, demonstrating Tarloxotinib bromide provides the necessary therapeutic index to inhibit WT EGFR in vivo[1].

[1]. Shevan Silva, Abstract A67: Preclinical efficacy of tarloxotinib bromide (TH-4000), a hypoxia-activated EGFR/HER2 inhibitor: rationale for clinical evaluation in EGFR mutant, T790M-negative NSCLC following progression on EGFR-TKI therapy. Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; November 5-9, 2015; Boston, MA. [2]. Adam V. Patterson, Abstract 5358: The hypoxia-activated EGFR-TKI TH-4000 overcomes erlotinib-resistance in preclinical NSCLC models at plasma levels achieved in a Phase 1 clinical trial. AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA.

Tarloxotinib 溴化物是一种不可逆的 EGFR/HER2 抑制剂。

为了确认作用机制，Tarloxotinib 溴化物在一组人类 NSCLC 细胞系（TKI 释放速率0.4-2.1 nM/hr/106 个细胞），一个被氧气抑制的过程（TKI 释放 80%（538 对 99 nM/kg；p

原型 WT EGFR 驱动的异种移植模型 (A431) 用于基准 Tarloxotinib 溴化物活性每个 EGFR-TKI 通过将人类受试者中每种药物的报告血浆暴露"逆转录"回异种移植模型。只有使用临床相关剂量和时间表的 Tarloxotinib 溴化物治疗才与肿瘤消退和 WT EGFR 肿瘤磷酸化的持久抑制相关。与这些发现一致，Tarloxotinib 溴化物治疗也可以使 WT EGFR NSCLC 肿瘤模型 H125 和 H1648 消退，证明 Tarloxotinib 溴化物提供了体内抑制 WT EGFR 的必要治疗指数[1]。