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Ref Type Abstract
PMID
Authors Ky-Youb Nam PhD * 1, Jeejin Im * 1, June H-J H-J Han * 1, Kyu-Tae Kim PhD * 1, Jeong-Hyeok Yoon PhD * 1, Hanna Cho PhD * 2, Seung-Hye Choi PhD * 2, David Young MD * 3, Bao Nguyen * 4, Ruiqi Zhu PhD * 5, Li Li MD,PhD * 4, Donald Small MD, PhD 5, Taebo Sim PhD * 2
Title PHI-101 Is a Potent Third-Generation FLT3 Inhibitor Developed to Overcome Resistance in Acute Myeloid Leukemia
Journal Vol Issue Date Pages Journal Short Title
Chemical Biology and Experimental Therapeutics 136 Supplement 1 November 2020
URL https://www.sciencedirect.com/science/article/pii/S0006497118724944
Abstract Text Background: FMS-like tyrosine kinase 3 (FLT3), a member of the class III receptor tyrosine kinase family, plays a pivotal role in regulating cell growth and differentiation of hematopoietic cells. FLT3 is mutated in approximately 30% of AML patients either by internal tandem duplication (ITD) within the juxtamembrane portion or by point-mutations in the kinase domain (TKD). Thus, FLT3 inhibitors including quizartinib (AC220), midostaurin (PKC412) and gilteritinib (ASP2215) have been developed and undergone clinical testing for the treatment of AML. However, patients frequently relapse due to intrinsic and extrinsic resistance to these FLT3 inhibitors in spite of the initial clinical efficacy. We have developed a potent third-generation FLT3 inhibitor, PHI-101, capable of overcoming some of these mechanisms of resistance. Methods: Biochemical kinase assays for PHI-101 have been performed on 9 different FLT3 mutants and wild type FLT3. Cellular potencies of PHI-101 have also been assessed using various patient-derived AML cells as well as MV4-11, MOLM14 and BaF3 cell lines transformed with human FLT3 mutants including single mutations [FLT3(ITD), FLT3(D835Y)], double or triple mutations [FLT3(ITD/D835Y), FLT3(ITD/F691L), FLT3(ITD/F691L/D835Y)]. In order to evaluate in vivo efficacies of oral administration of PHI-101, xenograft mouse models and in vivo bioluminescence imaging have been utilized. Results: PHI-101 possessed excellent enzymatic potencies against FLT3 potential resistant mutants such as ITD/D835V and the gatekeeper ITD/F691L mutation, as well as against FLT3 single activating mutants that include ITD, D835V, D835H, and D835Y. PHI-101 inhibited the phosphorylation of FLT3 and downstream STAT5 and ERK1/2 more effectively than quizartinib and gilteritinib at equivalent doses. Moreover, oral administration of PHI-101 induced tumor regression in the xenograft mouse models developed by injection of BaF3 cells transformed with FLT3-ITD, FLT3-TKD or FLT3-ITD/TKD mutants in a dose-dependent fashion with no appreciable toxicities. In luciferase-bearing blood circulating mouse models with FLT3-double mutants (ITD/D835Y and ITD/F691L) or triple mutants (ITD/D835Y/F691L), oral administration (30 mpk, QD) of PHI-101 diminished more than 89% of bioluminescent intensity and reduced leukemic burden. PHI-101 also showed increased efficacy in extending the lifespan of xenograft mice compared to quizartinib. PHI-101 strongly suppressed proliferation and induced apoptosis in primary AML samples harboring FLT3/ITD and FLT3/TKD mutations with little effect on wild-type FLT3 samples. Conclusion: PHI-101, an orally bioavailable novel small molecule, is a potent third-generation FLT3 inhibitor able to overcome resistance to several resistance mutations based on in vitro and in vivo experiments. PHI-101 possesses excellent in vitro and in vivo activities against not only FLT3 single activating mutations (ITD or TKD mutants) but also FLT3 double (ITD/D835Y or ITD/F691L) and triple (ITD/D835Y/F691L) resistant mutations with no pronounced toxicities. Preclinical evaluation of PHI-101 showed clear evidence of antileukemic activity and improved efficacy in both in vitro and in vivo models. PHI-101 is currently under investigation in first-in-human clinical trials with relapsed or refractory AML patients.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FLT3 exon 14 ins FLT3 F691L FLT3 D835Y hematologic cancer predicted - sensitive PHI-101 Preclinical - Cell line xenograft Actionable In a preclinical study, PHI-101 decreased leukemia burden in a cell line xenograft model expressing FLT3 D835Y and F691L in the context of a FLT3-ITD mutation (Blood (2020) 136 (Supplement 1): 802). detail...
FLT3 exon 14 ins hematologic cancer predicted - sensitive PHI-101 Preclinical - Cell line xenograft Actionable In a preclinical study, PHI-101 induced tumor regression in a cell line xenograft model expressing a FLT3-ITD mutation (Blood (2020) 136 (Supplement 1): 802). detail...
FLT3 exon 14 ins FLT3 F691L hematologic cancer predicted - sensitive PHI-101 Preclinical - Cell line xenograft Actionable In a preclinical study, PHI-101 decreased leukemia burden in a cell line xenograft model expressing FLT3 F691L in the context of a FLT3-ITD mutation (Blood (2020) 136 (Supplement 1): 802). detail...
FLT3 exon 14 ins acute myeloid leukemia predicted - sensitive PHI-101 Preclinical - Patient cell culture Actionable In a preclinical study, PHI-101 decreased proliferation and induced apoptosis in patient-derived acute myeloid leukemia samples harboring a FLT3-ITD mutation in culture (Blood (2020) 136 (Supplement 1): 802). detail...
FLT3 exon 14 ins FLT3 D835Y hematologic cancer predicted - sensitive PHI-101 Preclinical - Cell line xenograft Actionable In a preclinical study, PHI-101 decreased leukemia burden in a cell line xenograft model expressing FLT3 D835Y in the context of a FLT3-ITD mutation (Blood (2020) 136 (Supplement 1): 802). detail...