eltanexor (KPT-8602)

Unbiased combinatorial screening reveals co-inhibition of nuclear export and translation initiation as a vulnerability in metastatic castration-resistant prostate cancer. Dual targeting of XPO1 and EIF4A1 drives synergistic collapse of oncogenic protein networks, including AR/AR-V7 signaling, to overcome key resistance mechanisms and induce potent antitumor responses across heterogeneous models. Notably, these effects are achieved at substantially reduced doses using clinically tractable agents, defining a mechanistically grounded therapeutic strategy poised for rapid clinical translation.

XPO1 hyperactivation rewires nucleocytoplasmic transport and sustains leukaemogenic programs in genetically defined acute myeloid leukaemia (AML) subsets. Selective XPO1 inhibitors (selinexor, eltanexor) show preferential activity in NPM1-mutated, DEK::NUP214-positive and SF3B1-mutated myeloid neoplasms. Combination strategies with hypomethylating agents, BCL-2 inhibitors and other targeted therapies enhance depth and durability of responses but are limited by toxicity. Future clinical trials should focus on molecularly selected populations, biomarker-guided dosing and translational endpoints such as measurable residual disease (MRD) and clonal dynamics.

Preclinical studies showed a synergistic antileukemia activity with combination of selective XPO1 inhibitor selinexor (SEL) and venetoclax (VEN), with potential to overcome VEN resistance by reducing the anti-apoptotic protein MCL1. In conclusion, SEL-VEN was feasible and active in a heavily pretreated AML cohort, with no new toxicity signal, but survival outcomes remained poor. The second-generation XPO1-inhibitor eltanexor, combined with VEN may further improve outcomes in VEN resistant AML in an ongoing study (NCT06399640).

Recent advances have led to the development of novel therapeutic strategies, such as BCL-2 inhibitors (venetoclax), IDH1/2 inhibitors (ivosidenib, enasidenib), CD47 inhibitors (magrolimab), TIM-3 inhibitors (sabatolimab), XPO1 inhibitors (eltanexor), NEDD8-activating enzyme inhibitors (pevonedistat), TP53-targeted agents (eprenetapopt), liposomal chemotherapy (CPX-351), and oral HMA formulations. Combinations of hypomethylating agents with these new drugs, as first-line treatment, have to date not proven more efficacious than HMA monotherapy. This review summarizes the current therapeutic landscape on novel therapies for HR-MDS, highlighting their mechanism of action, efficacy, and demonstrates the unmet clinical need for more effective therapies.

The combination of KPT-8602 and IFN-γ can activate the pan-apoptotic pathway by upregulating ZBP1, thereby effectively inhibiting the growth of PCNSL. This study presented a promising new combination treatment strategy for PCNSL.

Here, we demonstrate that the second-generation XPO1 inhibitor Eltanexor synergizes with MRTX1133 to enhance its efficacy in multiple PDAC models. By enhancing KRASG12D inhibitor activity and potentially reducing the required therapeutic dose, this combination approach offers a novel means to delay or overcome resistance. These findings provide a strong preclinical rationale for clinical trials evaluating KRAS inhibitors in combination with XPO1 inhibitors and may significantly improve outcomes for a substantial subset of PDAC patients who currently lack effective targeted treatment options.

P1/2, N=3, Terminated, National Cancer Institute (NCI) | Completed --> Terminated; Drug company withdrew support.

Furthermore, we found that, like OCI-AML cells, the exportin 1 (XPO1) inhibitors selinexor and eltanexor significantly induced cell cycle arrest and reduced PHGDH expression in OCI-AML3-OR cells. Therefore, treatment with PHGDH inhibitors could be a therapeutic strategy for refractory AML to PI3K/mTOR inhibitors. Relevant clinical trials are warranted.

In this study, we screened nine XPO1 inhibitors, including the natural compounds curcumin, piperlongumine, plumbagin, and oridonin, as well as the synthetic agents KPT-185, KPT-276, selinexor, verdinexor, and eltanexor, in erythroid progenitors from patients with severe β0-thalassemia/HbE to identify the most effective inducer of TEM and to investigate the downstream molecular mechanisms involved...Combination treatments with hydroxyurea (a γ-globin inducer) and SIS3 (a SMAD3 inhibitor) confirmed selinexor's dominant effect...These findings suggest that cytoplasmic HSP70 trafficking may contribute to erythroid maturation in severe β0-thalassemia/HbE, implicating regulatory pathways beyond nuclear GATA1 stabilization. Collectively, our findings highlight the therapeutic potential of repurposing selinexor to enhance erythroid maturation in β-thalassemia and suggest that cytoplasmic HSP70 trafficking warrants further investigation as a contributor to terminal erythroid maturation in β-thalassemia.

These findings may provide guidance for development of clinical trial combination regimens including cirtuvivint, CC-671 or iadademstat. Full data sets are available on PubChem.

Here, we show that the XPO1 nuclear export inhibitor eltanexor significantly reduces atherosclerotic plaque formation in a mouse model of Tet2 -mutant CHIP...Tet2 loss diminished ATF3 binding to the regulatory loci of inflammatory mediators, which was restored upon XPO1 inhibition. These results provide new insights into drivers of heightened inflammation in TET2 -mutant CHIP and highlight a novel therapeutic strategy for intervention.