Eltanexor (KPT-8602)

Eltanexor, also known as KPT-8602, is a second-generation exportin-1 inhibitor. KPT-8602 demonstrates potent activity against acute lymphoblastic leukemia. KPT-8602 is well tolerated and highly active against AML blasts and leukemia-initiating cells. Eltanexor shows improved efficacy and in vivo tolerability in hematological malignancies.

KPT-8602 is a potent inhibitor of AML cells in cell-based viability assays[1]. KPT-8602 inhibits XPO1/cargo interactions and nuclear export, induces apoptosis of primary CLL cells and significantly inhibits proliferation of diffuse large B-cell lymphoma cell lines[2]

KPT-8602 is orally bioavailable and has similar pharmacokinetic properties to selinexor, but has markedly reduced (approximately 30-fold less) penetration across the blood−brain barrier. Toxicology studies in rats and monkeys indicate that KPT-8602 has a substantially better tolerability profile, probably due to its inability to penetrate into the CNS, with reduced anorexia, malaise and weight loss compared to selinexor.

KPT-8602 exhibits superior anti-leukemic activity and better tolerability in the AML PDX models tested, with nearly complete elimination of human AML cells in the AML-CN model. KPT-8602 is minimally toxic to normal hematopoietic stem and progenitor cells[1]. KPT-8602 does not accumulate in plasma after repetitive dosing and prolongs survival in a human leukemia xenograft model of AML[2].

Reference:

 [1] Etchin J, et al. Leukemia. 2017, 31(1):143-150.
 [2] Hing ZA, et al. Leukemia. 2016, 30(12):2364-2372.