TTI-101: A competitive inhibitor of STAT3 that spares oxidative phosphorylation and reverses mechanical allodynia in mouse models of neuropathic pain.
TTI-101: A competitive inhibitor of STAT3 that spares oxidative phosphorylation and reverses mechanical allodynia in mouse models of neuropathic pain.
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DOI：
10.1016/j.bcp.2021.114688
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发表时间：
2021-10
影响因子：
5.8
通讯作者：
Tweardy DJ
中科院分区：
文献类型：
--
作者：
Kasembeli MM;Singhmar P;Ma J;Edralin J;Tang Y;Adams C 3rd;Heijnen CJ;Kavelaars A;Tweardy DJ
信号转导和转录激活因子(STAT)3迅速成为治疗癌症的高价值靶点。然而，小分子STAT3抑制剂进入临床的速度一直很慢，部分原因是严重的不良事件，包括乳酸酸中毒和周围神经病变，这些不良事件被归因于STAT3‘S线粒体功能的抑制。我们的团队开发了TTI-101，这是一种STAT3的竞争性抑制剂，靶向于Src同源2(SH2)结构域中的受体pY705-肽结合部位，以阻止其招募和激活。在实体肿瘤患者的I期研究中，TTI-101已经显示出靶向性、无毒性和临床益处的证据。我们在此报告，TTI-101不影响线粒体功能，也不会引起STAT3聚集，也不会对STAT3进行化学修饰，也不会引起神经病理性疼痛。相反，TTI-101出人意料地抑制了化疗或备用神经损伤模型中引起的神经病理性疼痛。因此，除了其直接的抗肿瘤作用外，TTI-101在用于有发生化疗诱导的周围神经病变(CIPN)风险的癌症患者时可能是有益的。
Signal Transducer and Activator of Transcription (STAT) 3 emerged rapidly as a high-value target for treatment of cancer. However, small-molecule STAT3 inhibitors have been slow to enter the clinic due, in part, to serious adverse events (SAE), including lactic acidosis and peripheral neuropathy, which have been attributed to inhibition of STAT3′s mitochondrial function. Our group developed TTI-101, a competitive inhibitor of STAT3 that targets the receptor pY705-peptide binding site within the Src homology 2 (SH2) domain to block its recruitment and activation. TTI-101 has shown target engagement, no toxicity, and evidence of clinical benefit in a Phase I study in patients with solid tumors. Here we report that TTI-101 did not affect mitochondrial function, nor did it cause STAT3 aggregation, chemically modify STAT3 or cause neuropathic pain. Instead, TTI-101 unexpectedly suppressed neuropathic pain induced by chemotherapy or in a spared nerve injury model. Thus, in addition to its direct anti-tumor effect, TTI-101 may be of benefit when administered to cancer patients at risk of developing chemotherapy-induced peripheral neuropathy (CIPN).
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DOI：
10.1038/nrneurol.2014.77
发表时间：
2014-06
期刊：
Nature reviews. Neurology
影响因子：
--
作者：
Bennett GJ;Doyle T;Salvemini D
通讯作者：
Salvemini D
影响因子：
5.6
作者：
Kasembeli MM;Bharadwaj U;Robinson P;Tweardy DJ
通讯作者：
Tweardy DJ
影响因子：
45.3
作者：
Giantonio, Bruce J.;Catalano, Paul J.;Benson, Al B., III
通讯作者：
Benson, Al B., III
DOI：
10.1007/978-1-4939-9232-4_8
发表时间：
2019-01-01
期刊：
MASS SPECTROMETRY OF PROTEINS
影响因子：
--
作者：
Antinori, Paola;Michelot, Theo;Acosta-Martin, Adelina E.
通讯作者：
Acosta-Martin, Adelina E.
影响因子：
7.4
作者：
Ma, Jiacheng;Trinh, Ronnie T.;Kavelaars, Annemieke
通讯作者：
Kavelaars, Annemieke