A Novel Oral Selective Estrogen Receptor Degrader TFX06 Suppresses In Vivo Growth of ESR1 Wild-Type and Mutant Tumors

ER ⁺ breast cancer (BC) patients frequently develop drug resistance during the treatment with endocrine therapy (ET). One of the mechanisms for drug resistance is acquired ESR1 mutations. Thus, developing effective new ET overcoming drug resistance is urgently needed. We disclose herein TFX06, a novel and oral selective estrogen receptor degrader. TFX06 exhibited potent ERα antagonism, induced ERα degradation, and inhibited the proliferation of ESR1 wild-type and mutant BC cells in vitro . In vivo , TFX06 demonstrated single-agent antitumor activity, as well as synergized with palbociclib, against both ESR1 wild-type and mutant BC xenograft tumors in mice. In addition, TFX06 exhibited a pharmacokinetic-pharmacodynamic correlation in a xenograft tumor model. Furthermore, TFX06 did not stimulate the growth of uterine of immature rats, indicating that it’s a pure ER antagonist without agonist activity. Currently TFX06 is in phase I/II clinical development in patients to evaluate its safety and preliminary efficacy.