Abstract LB-109: Discovery of a highly potent and blood-brain barrier (BBB) penetrable second generation Pan-TRK/ROS1 dual inhibitor, XZP-5955
Authors: Sun Jun , Bai Shujin , Chen Bo , Dong Yuqi , Ding Yanwei , Hu Qian , Ma Xifeng , Nie Yanfang , Shi Chunmin , Sun Ying , Wei Zhaoqiang , Yang Xiping , Zhu Peng , Shi Chengkong , Li Jiakui , Shi Chongtie , Yao Zuliang , Liu Bin 
Published: September 2020

Abstract
Oncogenic TRK fusions are identified in various types of cancers including brain cancers in adults and children. Currently in clinic, first generation TRK inhibitors, such as larotrectinib and entrectinib, have demonstrated marked efficacy in patients with cancers carrying TRK fusions, however, like most kinase inhibitors, acquired resistance mediated by kinase domain mutations has occurred. To overcome the acquired resistances, second-generation TRK inhibitors, TPX-0005 and LOXO-195, targeting both wild-type and mutant TRK fusions are currently in clinical development. Both TPX-0005 and LOXO-195 have demonstrated efficacies in both pre-clinical animal models and clinical studies in patients. The potential shortcoming for both TRK inhibitors of TPX-0005 and LOXO-195 is their limited ability to penetrate blood-brain barrier (BBB) in order to effectively target TRK fusion related tumors inside brain. Here we report a highly potent and orally bioavailable pan-TRK/ROS1 dual inhibitor, XZP-5955. XZP-5955 shows high potency against a broad spectrum of TRK and ROS1 resistance mutations found in patients including TRKA G595R (IC50=2.2nM), TRKA G667C (IC50=1.0nM), TRKC G623R (IC50=4.7nM) and ROS1 G2032R (IC50 &lt; 0.05 nM). It also potently inhibits proliferations of rat BaF3 cells expressing oncogenic NTRK or ROS1 fusions and their resistant variants, such as TRKA G595R, TRKC G623R, TRKA G667C and ROS1 G2032R with high potency. XZP-5955 demonstrated superior potency in biochemical and cell assays to both TPX-0005 and LOXO-195. In in vivo, XZP-5955 is highly effıcacious against NTRK mutant cell line in xenograft models, and it is well tolerated in mice after repeated oral administration. In a BaF3 LMNA-TRKA G595R xenograft model, oral dosing at 1 mg/kg, 3 mg/kg and 10 mg/kg for 9 days, XZP-5955 demonstrated dose dependent inhibition of tumor growth and led to significant tumor regression or even complete tumor inhibition at 3mg/kg. In addition, XZP-5955 has good PK profile in multiple species. Noticeably, XZP-5955 demonstrates excellent brain penetration in rodent species, such as with brain/plasma ratio of 2.2 in rat. This is in contrast to the poor brain penetration observed with the other relevant inhibitors targeting TRKs. Preliminary toxicology studies in rat and dog demonstrated that XZP-5955 has desired margins of safety to warrant its further development. Based on the activity profile of XZP-5955 against clinically-relevant resistance mutations and its excellent brain penetration, this molecule has high potential to become a second-generation TRK kinase inhibitor especially for targeting brain tumors or brain metastatic lesions that harbor a NTRK gene fusion and ROS1 mutations. XZP-5955 is currently undergoing further characterizations in IND enabling studies. IND submission is expected by the end of 2020.
Citation Format: Jun Sun, Shujin Bai, Bo Chen, Yuqi Dong, Yanwei Ding, Qian Hu, Xifeng Ma, Yanfang Nie, Chunmin Shi, Ying Sun, Zhaoqiang Wei, Xiping Yang, Peng Zhu, Chengkong Shi, Jiakui Li, Chongtie Shi, Zuliang Yao, Bin Liu. Discovery of a highly potent and blood-brain barrier (BBB) penetrable second generation Pan-TRK/ROS1 dual inhibitor, XZP-5955 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-109.