AXL inhibitors(AXL receptor tyrosine kinase inhibitors), MerTK inhibitors(Tyrosine-protein kinase Mer inhibitors), TYRO3 inhibitors(TYRO3 protein tyrosine kinase inhibitors)

Therapeutic Areas

Neoplasms

Active Indication

Neoplasms

Inactive Indication

Advanced Malignant Solid NeoplasmSolid tumor

Originator Organization

Teva Pharmaceutical Industries Ltd.

Active Organization

Teva Pharmaceutical Industries Ltd.F. Hoffmann-La Roche Ltd.

Daiichi Sankyo Co., Ltd.

Inactive Organization

Hoffmann-La Roche, Inc.

Drug Highest PhasePhase 1

First Approval Date-

Regulation-

Structure

Molecular FormulaC31H26F2N4O6

InChIKeyFKCWHHYUMFGOPY-UHFFFAOYSA-N

CAS Registry1437321-24-8

Clinical Trials associated with RXDX-106

NCT03454243 / TerminatedEarly Phase 1

A Study of RXDX-106, an Oral Immunomodulatory TYRO3, AXL, and MER (TAM) Tyrosine Kinase Inhibitor, in Patients With Locally Advanced or Metastatic Solid Tumors

This is a first-in-human, open label, multicenter, dose escalation study of RXDX-106 in patients with locally advanced or metastatic solid tumors, who have no available therapy likely to convey clinical benefit.
This study will examine the safety, tolerability, pharmacokinetics (PK), pharmacodynamics and preliminary efficacy of RXDX 106.

Start Date15 Feb 2018

Sponsor / Collaborator

Hoffmann-La Roche, Inc.

100 Clinical Results associated with RXDX-106

100 Translational Medicine associated with RXDX-106

100 Patents (Medical) associated with RXDX-106

Literatures (Medical) associated with RXDX-106

01 Sep 2023·Journal of Dental Research

Inhibition of Mertk Signaling Enhances Bone Healing after Tooth Extraction

Article

Author: Shea, L.D. ; Kaigler, D. ; Inohara, N. ; Decker, A.M. ; Decker, J.T. ; Roh, A. ; Matsumoto, M. ; Martin, K. ; Núñez, G. ; Taichman, R. ; Sugai, J.

Regeneration of alveolar bone is an essential step in restoring healthy function following tooth extraction. Growth of new bone in the healing extraction socket can be variable and often unpredictable when systemic comorbidities are present, leading to the need for additional therapeutic targets to accelerate the regenerative process. One such target is the TAM family (Tyro3, Axl, Mertk) of receptor tyrosine kinases. These proteins have been shown to help resolve inflammation and maintain bone homeostasis and thus may have therapeutic benefits in bone regeneration following extraction. Treatment of mice with a pan-TAM inhibitor (RXDX-106) led to accelerated alveolar bone fill following first molar extraction in a mouse model without changing immune infiltrate. Treatment of human alveolar bone mesenchymal stem cells with RXDX-106 upregulated Wnt signaling and primed the cells for osteogenic differentiation. Differentiation of human alveolar bone mesenchymal stem cells with osteogenic media and TAM-targeted inhibitor RXDX-106 (pan-TAM), ASP-2215 (Axl specific), or MRX-2843 (Mertk specific) showed enhanced mineralization with pan-TAM or Mertk-specific inhibitors and no change with Axl-specific inhibitor. First molar extractions in Mertk–/– mice had increased alveolar bone regeneration in the extraction socket relative to wild type controls 7 d postextraction. Flow cytometry of 7-d extraction sockets showed no difference in immune cell numbers between Mertk –/– and wild type mice. RNAseq of day 7 extraction sockets showed increased innate immune-related pathways and genes associated with bone differentiation in Mertk –/– mice. Together, these results indicate that TAM receptor signaling, specifically through Mertk, can be targeted to enhance bone regeneration after injury.

01 Apr 2022·Molecular Cancer ResearchQ2 · MEDICINE

Integrated Proteomics-Based Physical and Functional Mapping of AXL Kinase Signaling Pathways and Inhibitors Define Its Role in Cell Migration

Q2 · MEDICINE

Article

Author: Saller, James J. ; Boyle, Theresa A. ; Haura, Eric B. ; Zhang, Guolin ; Smith, Matthew A. ; Stewart, Paul A. ; Hosseinian, Sina ; Welsh, Eric A. ; Meyer, Benjamin S. ; Kinose, Fumi ; Meyer, Aaron S. ; Koomen, John M. ; Creixell, Marc ; Adhikari, Emma ; Fang, Bin ; Bowers, Kiah ; Stroud, Mia ; Majumder, Anurima ; Agarwal, Shruti

AbstractTo better understand the signaling complexity of AXL, a member of the tumor-associated macrophage (TAM) receptor tyrosine kinase family, we created a physical and functional map of AXL signaling interactions, phosphorylation events, and target-engagement of three AXL tyrosine kinase inhibitors (TKI). We assessed AXL protein complexes using proximity-dependent biotinylation (BioID), effects of AXL TKI on global phosphoproteins using mass spectrometry, and target engagement of AXL TKI using activity-based protein profiling. BioID identifies AXL-interacting proteins that are mostly involved in cell adhesion/migration. Global phosphoproteomics show that AXL inhibition decreases phosphorylation of peptides involved in phosphatidylinositol-mediated signaling and cell adhesion/migration. Comparison of three AXL inhibitors reveals that TKI RXDX-106 inhibits pAXL, pAKT, and migration/invasion of these cells without reducing their viability, while bemcentinib exerts AXL-independent phenotypic effects on viability. Proteomic characterization of these TKIs demonstrates that they inhibit diverse targets in addition to AXL, with bemcentinib having the most off-targets. AXL and EGFR TKI cotreatment did not reverse resistance in cell line models of erlotinib resistance. However, a unique vulnerability was identified in one resistant clone, wherein combination of bemcentinib and erlotinib inhibited cell viability and signaling. We also show that AXL is overexpressed in approximately 30% to 40% of nonsmall but rarely in small cell lung cancer. Cell lines have a wide range of AXL expression, with basal activation detected rarely.Implications:Our study defines mechanisms of action of AXL in lung cancers which can be used to establish assays to measure drug targetable active AXL complexes in patient tissues and inform the strategy for targeting it's signaling as an anticancer therapy.

15 Apr 2019·Cancer ResearchQ1 · MEDICINE

Immuno-oncological Efficacy of RXDX-106, a Novel TAM (TYRO3, AXL, MER) Family Small-Molecule Kinase Inhibitor

Q1 · MEDICINE

Article

Author: Smith, Kristen M. ; Bui, Jack D. ; Yokoyama, Yumi ; Li, Gary ; Tucker, Kathleen D. ; Albert, Amanda ; Lee, Jack Y. ; Vaaler, Heather ; Walsh, Colin ; Diliberto, Amy ; Seelige, Ruth ; Tindall, Elizabeth A. ; Chen, Marissa ; Nevarez, Robin ; Fagan, Patrick C. ; Oh, Joanne ; Lew, Erin D.

AbstractExpression of the TAM (TYRO3, AXL, MER) family of receptor tyrosine kinases (RTK) has been associated with cancer progression, metastasis, and drug resistance. In immune cells, TAM RTKs can dampen inflammation in favor of homeostatic wound-healing responses, thus potentially contributing to the evasion of cancer cells from immune surveillance. Here we characterize the small-molecule RXDX-106 as a selective and potent pan-TAM RTK inhibitor with slow dissociation kinetics and significant antitumor activity in multiple syngeneic tumor models. Expression of AXL and MER on both immune and tumor cells increased during tumor progression. Tumor growth inhibition (TGI) following treatment with RXDX-106 was observed in wild-type mice and was abrogated in immunodeficient mice, suggesting that the antitumor activity of RXDX-106 is, in part, due to the presence of immune cells. RXDX-106–mediated TGI was associated with increased tumor-infiltrating leukocytes, M1-polarized intratumoral macrophages, and activation of natural killer cells. RXDX-106 proportionally increased intratumoral CD8+ T cells and T-cell function as indicated by both IFNγ production and LCK phosphorylation (pY393). RXDX-106 exhibited its effects via direct actions on TAM RTKs expressed on intratumoral macrophages and dendritic cells, leading to indirect activation of other immune cells in the tumor. RXDX-106 also potentiated the effects of an immune checkpoint inhibitor, α-PD-1 Ab, resulting in enhanced antitumor efficacy and survival. Collectively, these results demonstrate the capacity of RXDX-106 to inhibit tumor growth and progression and suggest it may serve as an effective therapy against multiple tumor types.Significance:The pan-TAM small-molecule kinase inhibitor RXDX-106 activates both innate and adaptive immunity to inhibit tumor growth and progression, indicating its clinical potential to treat a wide variety of cancers.

100 Deals associated with RXDX-106

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Malignant Solid Neoplasm	Phase 1	US	Hoffmann-La Roche, Inc.	15 Feb 2018
Solid tumor	Phase 1	US	F. Hoffmann-La Roche Ltd.	15 Feb 2018
Neoplasms	Phase 1	-	F. Hoffmann-La Roche Ltd.	-
Neoplasms	Phase 1	-	Daiichi Sankyo Co., Ltd.	-
Neoplasms	Phase 1	-	Teva Pharmaceutical Industries Ltd.	-

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