CDK4 inhibitors(Cyclin-dependent kinase 4 inhibitors), CDK6 inhibitors(Cyclin-dependent kinase 6 inhibitors), FLT3 inhibitors(Tyrosine-protein kinase receptor FLT3 inhibitors)

Therapeutic Areas

NeoplasmsHemic and Lymphatic Diseases

Active Indication

Acute Myeloid LeukemiaNeoplasms

Inactive Indication

Refractory acute myeloid leukemiaRelapsing acute myeloid leukemia

Originator Organization

Amgen, Inc.

Active Organization

Computational Biology Corp.

Amgen, Inc.

Inactive Organization

Rapt Therapeutics, Inc.

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC26H29N7O2

InChIKeyBBUVDDPUURMFOX-SAABIXHNSA-N

CAS Registry1401033-86-0

Clinical Trials associated with FLX-925

NCT02335814

/ TerminatedPhase 1

Phase 1/1b, First-in-Human, Dose-Escalation and Expansion Study of FLX925 Administered Orally to Subjects With Relapsed or Refractory Acute Myeloid Leukemia

This first-in-human (FIH) clinical trial is a Phase 1/1b, open-label, sequential-group, dose-escalation and cohort expansion study evaluating the safety, PK, PD, and antitumor activity of FLX925 in subjects with relapsed or refractory AML.

Start Date08 Apr 2015

Sponsor / Collaborator

Rapt Therapeutics, Inc.

100 Clinical Results associated with FLX-925

100 Translational Medicine associated with FLX-925

100 Patents (Medical) associated with FLX-925

Literatures (Medical) associated with FLX-925

01 Jun 2021·Annals of HematologyQ3 · MEDICINE

High-throughput proteomic profiling reveals mechanisms of action of AMG925, a dual FLT3-CDK4/6 kinase inhibitor targeting AML and AML stem/progenitor cells

Q3 · MEDICINE

Article

Author: Konopleva, Marina ; Cortes, Jorge ; Kantarjian, Hagop M ; Andreeff, Michael ; Zeng, Zhihong ; Daver, Naval ; Ly, Charlie

FLT3 mutations, which are found in a third of patients with acute myeloid leukemia (AML), are associated with poor prognosis. Responses to currently available FLT3 inhibitors in AML patients are typically transient and followed by disease recurrence. Thus, FLT3 inhibitors with new inhibitory mechanisms are needed to improve therapeutic outcomes. AMG925 is a novel, potent, small-molecule dual inhibitor of FLT3 and CDK4/6. In this study. we determined the antileukemic effects and mechanisms of action of AMG925 in AML cell lines and primary samples, in particular AML stem/progenitor cells. AMG925 inhibited cell growth and promoted apoptosis in AML cells with or without FLT3 mutations. Reverse-phase protein array profiling confirmed its on-target effects on FLT3-CDK4/6-regulated pathways and identified unrevealed signaling network alterations in AML blasts and stem/progenitor cells in response to AMG925. Mass cytometry identified pathways that may confer resistance to AMG925 in phenotypically defined AML stem/progenitor cells and demonstrated that combined blockade of FLT3-CDK4/6 and AKT/mTOR signaling facilitated stem cell death. Our findings provide a rationale for the mechanism-based inhibition of FLT3-CDK4/6 and for combinatorial approaches to improve the efficacy of FLT3 inhibition in both FLT3 wild-type and FLT3-mutated AML.

01 Dec 2018·Journal of Hematology & OncologyQ1 · MEDICINE

FLT3 inhibitors in acute myeloid leukemia

Q1 · MEDICINE

ReviewOA

Author: Li, Chuntuan ; Zhu, Xiongpeng ; Wu, Mei

FLT3 mutations are one of the most common findings in acute myeloid leukemia (AML). FLT3 inhibitors have been in active clinical development. Midostaurin as the first-in-class FLT3 inhibitor has been approved for treatment of patients with FLT3-mutated AML. In this review, we summarized the preclinical and clinical studies on new FLT3 inhibitors, including sorafenib, lestaurtinib, sunitinib, tandutinib, quizartinib, midostaurin, gilteritinib, crenolanib, cabozantinib, Sel24-B489, G-749, AMG 925, TTT-3002, and FF-10101. New generation FLT3 inhibitors and combination therapies may overcome resistance to first-generation agents.

01 Feb 2015·Molecular Cancer Therapeutics

AMG 925 Is a Dual FLT3/CDK4 Inhibitor with the Potential to Overcome FLT3 Inhibitor Resistance in Acute Myeloid Leukemia

Article

Author: Liu, Liqin ; Kamb, Alexander ; Li, Zhihong ; Li, Cong ; Sinclair, Angus ; McGee, Lawrence R. ; Wickramasinghe, Dineli ; Liang, Lingming ; Dai, Kang ; Newhall, Katie ; Wang, Xianghong ; Xia, Zhen

Resistance to FLT3 inhibitors is a serious clinical issue in treating acute myelogenous leukemia (AML). AMG 925, a dual FLT3/CDK4 inhibitor, has been developed to overcome this resistance. It is hypothesized that the combined inhibition of FLT3 and CDK4 may reduce occurrence of the FLT3 resistance mutations, and thereby prolong clinical responses. To test this hypothesis, we attempted to isolate AML cell clones resistant to AMG 925 or to FLT3 inhibitors. After a selection of over 8 months with AMG 925, we could only isolate partially resistant clones. No new mutations in FLT3 were found, but a 2- to 3-fold increase in total FLT3 protein was detected and believed to contribute to the partial resistance. In contrast, selection with the FLT3 inhibitors sorafenib or AC220 (Quizartinib), led to a resistance and the appearance of a number of mutations in FLT3 kinase domains, including the known hot spot sites D835 and F691. However, when AC220 was combined with the CDK4 inhibitor PD0332991 (palbociclib) at 0.1 μmol/L or higher, no resistance mutations were obtained, indicating that the CDK4-inhibiting activity of AMG 925 contributed to the failure to develop drug resistance. AMG 925 was shown to potently inhibit the FLT3 inhibitor-resistant mutation D835Y/V. This feature of AMG 925 was also considered to contribute to the lack of resistance mutations to the compound. Together, our data suggest that AMG 925 has the potential to reduce resistance mutations in FLT3 and may prolong clinical responses.

100 Deals associated with FLX-925

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Refractory acute myeloid leukemia	Phase 2	US	Rapt Therapeutics, Inc.	08 Apr 2015
Relapsing acute myeloid leukemia	Phase 2	US	Rapt Therapeutics, Inc.	08 Apr 2015
Neoplasms	Preclinical	US	Amgen, Inc.	02 Apr 2014
Acute Myeloid Leukemia	Preclinical	-	Amgen, Inc.	-

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