Abstract 1462: KF1601, a novel orally bioavailable inhibitor of Bcr-Abl T315I, without inducing thrombotic microangiopathy

Targeting Bcr-Abl with tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of chronic myeloid leukemia (CML) by significantly improving patients' survival. However, the gatekeeper mutation T315I confers resistance to TKIs targeting Bcr-Abl, presenting a formidable task in CML's clinical management. Ponatinib is the only approved drug for Bcr-AblT315I, but often accompanies severe, life-threatening side effects. Herein, we report KF1601, a novel orally bioavailable TKI: 1) KF1601 inhibited kinase functions of both Bcr-AblWT and Bcr-AblT315I with nanomolar IC50 values; 2) In xenograft models using Ba/F3 Bcr-AblT315I cell line, it showed promising in vivo antitumor efficacy, comparable to that of ponatinib; 3) In animal models, it did not cause thrombotic microangiopathy, a major mechanism of ponatinib's toxicity. In summary, KF1601 is a promising drug candidate for safely treating CML patients with drug-resistant Bcr-AblT315I mutation. Citation Format: HyunJin Kwon, Sung-Min Ahn, Kiho Chang, WooSik Kim, Amir Khan, Doohyun LEE, Seungyeon Lee, Ye Ri Han, Chun Young Im. KF1601, a novel orally bioavailable inhibitor of Bcr-Abl T315I, without inducing thrombotic microangiopathy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1462.