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Ref Type Abstract
PMID
Authors Ky-Youb Nam; Jeejin Im; JeongHyeok Yoon; David Young; Li Li; Ruiqi Zhu; Bao Nguyen; Donald Small
Title Abstract 4226: PHI-101, a next generation FLT3 inhibitor for acute myeloid leukemia
Journal Vol Issue Date Pages Journal Short Title
Cancer Research 80 16_Supplement August 15, 2020
URL https://aacrjournals.org/cancerres/article/80/16_Supplement/4226/643075/Abstract-4226-PHI-101-a-next-generation-FLT3
Abstract Text Purpose: Develop a next generation FLT3 TKI to overcome previous resistance mechanisms. Description: Preclinical testing of PHI-101 for efficacy against FLT3 mutations both in vitro and in vivo in cell lines and primary FLT3 mutant leukemia samples. Summary: Mutations in the FLT3 gene are common in AML, occurring in approximately 1/3 of patients and result in poor prognosis for AML patients with FLT3 internal tandem duplication (ITD) mutations. Thus, it is a well-validated target for the development of tyrosine kinase inhibitors (TKI). A number of FLT3 TKI have been developed and the latest generation have proven increasingly successful at achieving thorough inhibition of FLT3 kinase activity in vivo, a necessary requirement for clinical efficacy against FLT3 mutant AML. Major reasons for the failure of some FLT3 TKI to achieve thorough inhibition include tight binding to alpha 1 acid glycoprotein (AGP) resulting in inadequate free levels of the drug and selection for resistance mutations within FLT3 itself. Resistance mutations within FLT3 have included those at D835 and F691 among others. We present here the initial preclinical data on a new FLT3 TKI, PHI-101, developed to overcome some of these mechanisms of resistance. PHI-101 is a potent small molecule inhibitor of both FLT3/ITD and FLT3/D835Y mutations with an IC50 of 5 nM and 11.1 nM, respectively, in cell-based assays. It is active against a number of FLT3/ITD resistance mutations including FLT3/ITD/A627T, FLT3/ITD/N676D, FLT3/ITD/F691L, with IC50s of 0.1nM, 2.3nM, 14.6nM, respectively. It is also active against FLT3 kinase domain (FLT3/KD) resistance mutations, with IC50s against FLT3/D835A and FLT3/840GS of 5.3nM and 9.6nM, respectively. Furthermore, it is active against the FLT3/ITD/KD and FLT3/ITD/F691 resistance mutations. We also demonstrate its effectiveness in inhibiting FLT3 activity by Western blot analysis. Importantly, when analyzed in the human plasma inhibitory assay (PIA), its IC50 shifts only 8.5-fold, unlike several other FLT3 TKI with shifts of >200-fold, rendering them unable to sufficiently inhibit FLT3 mutations in vivo. PHI-101 monotherapy induces dose-dependent regression of tumor growth measured with bioluminescence in FLT3-ITD mutant xenograft models. In addition, PHI-101 significantly inhibits proliferation and induces apoptosis in primary AML samples expressing FLT3/ITD and FLT3/KD mutations, but not wild-type FLT3. These effects suggest it is selective for primary AML with FLT3 mutations, comparable to that of Giltertinib, the newly-approved FLT3 TKI. PHI-101 will soon undergo first-in-human clinical trials in FLT3 mutant AML patients. Conclusion: PHI-101 is a new FLT3 TKI with characteristics that warrant entry into human trials.

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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
PHI-101 PHI-101 9 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
PHI-101 PHI101|PHI 101 CHK2 Inhibitor 7 FLT3 Inhibitor 69 PHI-101 is a Chk2 inhibitor with additional activity against FLT3, which potentially results in antitumor activity (Cancer Res 2021;81(13_Suppl):Abstract nr 1461, Cancer Res 2020;80(16 Suppl):Abstract nr 4226).
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 A627T hematologic cancer predicted - sensitive PHI-101 Preclinical - Biochemical Actionable In a preclinical study, PHI-101 demonstrated activity against FLT3 A627T in the context of a FLT3-ITD mutation in culture (Cancer Res 2020;80(16 Suppl):Abstract nr 4226). detail...
FLT3 exon 14 ins FLT3 D835A hematologic cancer predicted - sensitive PHI-101 Preclinical - Biochemical Actionable In a preclinical study, PHI-101 demonstrated activity against FLT3 D835A in the context of a FLT3-ITD mutation in culture (Cancer Res 2020;80(16 Suppl):Abstract nr 4226). detail...
FLT3 exon 14 ins FLT3 N676D hematologic cancer predicted - sensitive PHI-101 Preclinical - Biochemical Actionable In a preclinical study, PHI-101 demonstrated activity against FLT3 N676D in the context of a FLT3-ITD mutation in culture (Cancer Res 2020;80(16 Suppl):Abstract nr 4226). detail...
FLT3 exon 14 ins FLT3 F691L hematologic cancer predicted - sensitive PHI-101 Preclinical - Biochemical Actionable In a preclinical study, PHI-101 demonstrated activity against FLT3 F691L in the context of a FLT3-ITD mutation in culture (Cancer Res 2020;80(16 Suppl):Abstract nr 4226). detail...