Table 1 Pre-clinical in vitro and in vivo studies of KPT compounds on hematological malignancies
From: XPO1 in B cell hematological malignancies: from recurrent somatic mutations to targeted therapy
Disease | XPO1 gene and protein | SINE | Effects | Reference |
|---|---|---|---|---|
AML | Â | KPT-185 | Induces apoptosis Promotes cell cycle arrest and inhibits proliferation Decreases XPO1 level and restores nuclear export Downregulates FLT3 and KIT oncogenes expression | [79] |
| Â | Â | KPT-276 | Increases survival of FLT3-ITD+-MV4.11 mice | Â |
CLL | High XPO1 expression | KPT-185 | Inhibits nuclear export Induces apoptosis of tumor cells not of normal B cells Targets the IκB pathway Antagonizes microenvironment stimuli (TNF, IL6, IL4) Inhibits tumor growth in vivo (Eμ-TCL1-SCID model) | [9] |
T-ALL | Â | KPT-185 | Induce apoptosis in vitro and in vivo | [8] |
| Â | Â | KPT-330 | Promote cell cycle arrest in G1 Inhibit tumor growth in vivo | Â |
AML | High XPO1 expression | KPT-185 | Inhibits nuclear export Induces a p53-dependent cell apoptosis Inhibits cell proliferation in a p53-idependent manner | Â |
AML | Â | KPT-330 | Inhibits XPO1/cargo interactions and nuclear export | |
| Â | Â | KPT-251 | Induces apoptosis Promotes cell cycle arrest in G1 Inhibits tumor growth in vivo Inhibits tumor growth in vivo | Â |
MCL | High XPO1 expression | KPT-185 | Blocks nuclear export | [71] |
|  |  | KPT-276 | Induces apoptosis in a p53-independent manner Has no effect on cell cycle Inactivates the NF-κB pathway Inhibits tumor growth in vivo |  |
MM | High XPO1 expression | KPT-276 | Induces cell apoptosis in vitro and in vivo Targets c-Myc, CDC25A, and BRD4 Induces cell cycle arrest in G1 | [70] |
MM | High XPO1 expression | KPT-185 | Inhibit nuclear export | [73] |
|  |  | KPT-330 | Induce apoposis and alleviate CAM-DR Promote cell cycle arrest in G1 Target c-Myc, MCL1, and NF-κB pathway Show a strong anti-myeloma activity in vivo, impair osteoclastogenesis and bone resorption |  |
NHL | Â | KPT-185 | Inhibits cell growth Induces apoptosis Restores the nuclear localization of TSPs and their function Shows anti-tumor activity in vivo | [101] |
Ph + ALL | High XPO1 expression | KPT-330 | Induces apoptosis both p53-dependent and -independent Decreases clonogenic potential Increases survival of BCR-ABL1 mice Alters the localization of hnRNP A1 and SET Reactivates the TSP PP2A | [102] |
CLL | Â | KPT-330 | Suppresses effectors of BCR signaling in vitro and in vivo via BTK depletion Prevents CLL cells migration | [103] |
HL | Mutation E571K XPO1 amplification | KPT-185 | Inhibits cell line proliferation and induces apoptosis whatever XPO1 status | [16] |
PMBL | Mutation E571K XPO1 amplification | KPT-185 | Inhibits cell line proliferation and induces apoptosis whatever XPO1 status | [12] |
AML/CLL/DLBCL |  | KPT-8602 | Inhibits XPO1/cargo interactions and nuclear export Induces apoptosis of primary CLL cells Inhibits proliferation of DLBCL cell lines (ABC and GC subtypes) Prolongs the survival of Eμ-TCL1 mice Acts in synergy with ibrutinib in vivo Inhibits proliferation and induces apoptosis of AML cell lines and primary blasts Is efficient in a mouse model of AML | [85] |