AXL Receptor Tyrosine Kinase as a Therapeutic Target in Hematological Malignancies: Focus on Multiple Myeloma

Abstract

AXL belongs to the TAM (TYRO3, AXL, and MERTK) receptor family, a unique subfamily of the receptor tyrosine kinases. Their common ligand is growth arrest-specific protein 6 (GAS6). The GAS6/TAM signaling pathway regulates many important cell processes and plays an essential role in immunity, hemostasis, and erythropoiesis. In cancer, AXL overexpression and activation has been associated with cell proliferation, chemotherapy resistance, tumor angiogenesis, invasion, and metastasis; and has been correlated with a poor prognosis. In hematological malignancies, the expression and function of AXL is highly diverse, not only between the different tumor types but also in the surrounding tumor microenvironment. Most research and clinical evidence has been provided for AXL inhibitors in acute myeloid leukemia. However, recent studies also revealed an important role of AXL in lymphoid leukemia, lymphoma, and multiple myeloma. In this review, we summarize the basic functions of AXL in various cell types and the role of AXL in different hematological cancers, with a focus on AXL in the dormancy of multiple myeloma. In addition, we provide an update on the most promising AXL inhibitors currently in preclinical/clinical evaluation and discuss future perspectives in this emerging field.

Design and Synthesis of 5‐Aryl‐substituted Phenylpyrimidine‐2,4‐diamine Derivatives as Novel Mer and Tyro3 Kinase Inhibitors

“…(Scheme 1) The N-Boc protecting group was transformed to a trifluoroacetyl group (4) to secure the next transformation. Various phenyl or aromatic groups (5) were introduced by palladium-catalyzed cross coupling conditions with R 1 -boronic acids. Treatment of compound 5 with aromatic amines yielded 2,2,2-trifluoro-1-(4-((5-phenyl-2-(phenylamino)pyrimidin-4-yl)amino)piperi-din-1-yl) ethan-1-one (6).…”

“…The water layer was extracted with EtOAc twice, and the organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure. 1-(4-((2-Chloro-5-phenylpyrimidin-4-yl)amino)piperidin-1-yl)-2,2,2-trifluoroethan-1-one (5). 1-(4-((5-Bromo-2-chloropyrimidin-4-yl)amino)piperidin-1-yl)-2,2,2-trifluoroethan-1-one (200 mg, 0.51 mmol, 1.0 eqiv) was dissolved in DMF (2 mL) then phenylboronic acid (94 mg, 0.77 mmol, 1.5 eqiv), Pd(dppf) 2 Cl 2 (19 mg, 0.02 mmol, 0.05 eqiv), K 2 CO 3 (164 mg, 1.55 mmol, 3.0 eqiv) were added and stirred at 80 C for 12 h. After the completion of the reaction, the reaction mixture was extracted twice, and the combined organic extracts were dried (Na 2 SO Induced Fit Docking.…”

“…4 Therefore, TAM receptors have been considered attractive targets for cancer therapy. Since the discovery of important roles of TAM receptors in cancer progression 5 and macrophages in the immune system of tumor microenvironment (TME), 6 there has been a variety of efforts in developing either pan-TAM inhibitors or selective TAM kinase inhibitors. 7 (Figure 1).…”

Structure-activity relationship of 7-aryl-2-anilino-pyrrolopyrimidines as Mer and Axl tyrosine kinase inhibitors

“…Recent studies revealed that Axl is a key molecule in hematological malignancies including multiple myeloma 7 and metastatic breast cancer 8 . The combination of a pan-TAM kinase inhibitor, BMS-777607, with anti-PD1 resulted in a better anti-tumour effect than each monotherapy alone in a mouse model 9 .…”

Latest Development in Multiple Myeloma

“…Yan et al reviewed the role of AXL , a member of the TYRO3/AXL/MERTK receptor tyrosine kinase family, in solid cancers and hematological malignancies [ 4 ]. AXL is involved in the regulation of cell survival, proliferation, angiogenesis, and immune modulation.…”