This is a phase II, Single-arm,Open-label Study evaluating the safety and efficacy of CT053PTSA in Advanced Solid Tumors With MET Exon 14 Skipping Mutations

Start Date27 Nov 2022

Sponsor / Collaborator

Sunshine Lake Pharma Co., Ltd.

NCT04872478

/ RecruitingPhase 1

An Open Label Evaluation Phase 1 Trial of the Safety and Pharmacokinetics of MRX-2843 in Adolescents and Adults with Relapsed/Refractory Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Mixed Phenotype Acute Leukemia

This is a Phase I, open-label, non-randomized, dose escalation study in adolescents and adults with relapsed/refractory acute myeloid leukemia, acute lymphoblastic leukemia, or mixed phenotype acute leukemia. Patients will receive continuous oral MRX-2843 in 28 day cycles at predefined dose cohorts.

Start Date01 Apr 2022

Sponsor / Collaborator

Meryx, Inc.

NCT04946890

/ Not yet recruitingPhase 1/2

Phase I/II Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Effectiveness of MRX2843 Tablets in Patients With Relapsed/Refractory Acute Myeloid Leukemia

Patients will receive oral MRX2843 for 28 days to study the side effects, tolerability and best dose for treating relapsed or refractory acute myeloid leukemia With FLT3 Mutations.

Start Date01 Jul 2021

Sponsor / Collaborator

Betta Pharmaceuticals Co., Ltd.

100 Clinical Results associated with FLT3 x MerTK

100 Translational Medicine associated with FLT3 x MerTK

0 Patents (Medical) associated with FLT3 x MerTK

Literatures (Medical) associated with FLT3 x MerTK

24 Apr 2025·Journal of Medicinal Chemistry

Discovery of Novel TYRO3/MERTK Dual Inhibitors

Article

Author: Zhou, Yubai ; Guduru, Shiva K. R. ; Yan, Dan ; Shelton Earp, H. ; Zhao, Jichen ; Frye, Stephen V. ; Kania, Catherine E. ; Stashko, Michael A. ; Kong, Deyu ; Huang, Daowei ; DeRyckere, Deborah ; Graham, Douglas K. ; Wang, Xiaodong ; Kireev, Dmitri ; Ding, Ransheng ; Huelse, Justus M.

The TAM (TYRO3, AXL, MERTK) family of receptor tyrosine kinases has roles in oncogenesis and innate immunity, but the relative importance of the family members can differ in different contexts and between tumor types or individual tumors. Dual TYRO3 and MERTK inhibition may be advantageous for treatment of diseases or in tumors that are dependent on their coordinated action. Here, we report the discovery of the first potent dual TYRO3/MERTK inhibitor, UNC9435 (44). UNC9435 has 46-fold and 120-fold selectivity of MERTK over AXL and FLT3, respectively, and selectively against a panel of 30 other kinases. TYRO3 and MERTK inhibitory activities were confirmed by NanoBRET assays in HEK293 cells, with <0.51 nM EC₅₀ values for both enzymes and >3000-fold selectivity over AXL. UNC9435 also inhibited TYRO3, MERTK, and downstream oncogenic signaling in cancer cells and reduced colony formation in non-small cell lung cancer cultures, indicating its potential as a novel cancer therapeutic.

01 Sep 2024·Leukemia Research

Combining the novel FLT3 and MERTK dual inhibitor MRX-2843 with venetoclax results in promising antileukemic activity against FLT3-ITD AML

Article

Author: Wang, Guan ; Hüttemann, Maik ; Edwards, Holly ; Carter, Jenna ; Liu, Fangbing ; Taub, Jeffrey W ; Li, Chunhuai ; Wu, Shuangshuang ; Wang, Yue ; Ge, Yubin ; Gai, Yuqing

FMS-like tyrosine kinase 3 (FLT3) mutations occur in approximately one third of acute myeloid leukemia (AML) patients. FLT3-Internal tandem duplication (FLT3-ITD) mutations are the most common FLT3 mutations and are associated with a poor prognosis. Gilteritinib is a FLT3 inhibitor that is US FDA approved for treating adult patients with relapsed/refractory AML and a FLT3 mutation. While gilteritinib monotherapy has improved patient outcome, few patients achieve durable responses. Combining gilteritinib with venetoclax (VEN) appears to make further improvements, though early results suggest that patients with prior exposure to VEN fair much worse than those without prior exposure. MRX-2843 is a promising inhibitor of FLT3 and MERTK. We recently demonstrated that MRX-2843 is equally potent as gilteritinib in FLT3-ITD AML cell lines in vitro and primary patient samples ex vivo. In this study, we investigated the combination of VEN and MRX-2843 against FLT3-ITD AML cells. We found that VEN synergistically enhances cell death induced by MRX-2843 in FLT3-mutated AML cell lines and primary patient samples. Importantly, we found that VEN synergistically enhances cell death induced by MRX-2843 in FLT3-ITD AML cells with acquired resistance to cytarabine (AraC) or VEN+AraC. VEN and MRX-2843 significantly reduce colony-forming capacity of FLT3-ITD primary AML cells. Mechanistic studies show that MRX-2843 decreases Mcl-1 and c-Myc protein levels via transcriptional regulation and combined MRX-2843 and VEN significantly decreases oxidative phosphorylation in FLT3-ITD AML cells. Our findings highlight a promising combination therapy against FLT3-ITD AML, supporting further in vitro and in vivo testing.

11 Apr 2024·Journal of Medicinal Chemistry

Discovery of Novel Macrocyclic MERTK/AXL Dual Inhibitors

Article

Author: Chen, Zhilong ; Wang, Xiaodong ; Kireev, Dmitri ; Earp, H. Shelton ; Zheng, Hongchao ; Frye, Stephen V. ; Stashko, Michael A. ; DeRyckere, Deborah ; Kong, Deyu ; Tian, Qiang ; Yan, Dan ; Graham, Douglas K.

MERTK and AXL are members of the TAM (TYRO3, AXL, MERTK) family of receptor tyrosine kinases that are aberrantly expressed and have been implicated as therapeutic targets in a wide variety of human tumors. Dual MERTK and AXL inhibition could provide antitumor action mediated by both direct tumor cell killing and modulation of the innate immune response in some tumors such as nonsmall cell lung cancer. We utilized our knowledge of MERTK inhibitors and a structure-based drug design approach to discover a novel class of macrocyclic dual MERTK/AXL inhibitors. The lead compound 43 had low-nanomolar activity against both MERTK and AXL and good selectivity over TYRO3 and FLT3. Its target engagement and selectivity were also confirmed by NanoBRET and cell-based MERTK and AXL phosphorylation assays. Compound 43 had excellent pharmacokinetic properties (large AUC and long half-life) and mediated antitumor activity against lung cancer cell lines, indicating its potential as a therapeutic agent.

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