KPT-8602, a second-generation selective inhibitor of nuclear export (SINE), demonstrated similar anti-leukemic activity and better tolerability than the first-generation SINE selinexor, according to early results from an in vitro study presented at the AACR Annual Meeting. The novel agent also showed high specificity for its target, the exportin-1 (XPO1) gene.
“XPO1 is the key nuclear-cytoplasmic transport protein that exports a wide variety of different cargo proteins, including tumor suppressors, out of the cell’s nucleus,” the authors, led by Dirk Daelemans, from the Rega Institute for Medical Research at the University of Leuven in Belgium, explained. “Inhibition of XPO1 function consequently restores nuclear localization of these proteins and is a promising therapeutic strategy for cancer.”
In phase II/IIb clinical trials, selinexor, the oral first-generation SINE, led to remissions in patients with acute lymphocytic leukemia (ALL), both as a single agent and in combination with other therapies. While selinexor was well tolerated when dosed one to three times a week (administered every other day when dosed), KPT-8602 has an improved safety profile, the authors noted, and may allow for more frequent dosing.
Researchers first assessed the anti-XPO1 activity of KPT-8602, finding that the SINE “potently inhibited” XPO1-mediated nuclear protein export at nanomolar concentrations and blocked the interaction of XPO1 with cargo protein.
“KPT-8602 also induced potent cytotoxicity on a panel of T-ALL and B-ALL cell lines,” Mr. Daelemans and colleagues noted. This cytotoxicity correlated with the induction of caspase-dependent apoptosis and the nuclear accumulation of p53, as well as the subsequent induction of p53 response.
The researchers then applied CRISPR/Cas9 technology to further characterize KPT-8602’s mechanism of action; after introducing a Cys528Ser mutation in the XPO1 gene of four different leukemia cell lines, they observed that mutant cells were >100 times more resistant to KPT-8602. Drug-target interaction was also confirmed via a pull-down assay of wild-type XPO1 protein.
“These results illustrate the highly specific interaction of the drug for its target and prove that the anti-leukemic activity of KPT-8602 is caused by inhibition of XPO1,” the researchers noted.
Mr. Daelemans and researchers also examined KPT-8602’s anti-leukemic activity in vivo, in mice engrafted with patient-derived T-cell ALL. The mice received either KPT-8602 or placebo daily for three weeks, and blood counts were measured weekly. Compared with placebo-treated animals, KPT-8602 led to a substantial reduction in leukemia cell numbers in the blood, without affecting normal erythropoiesis, and resulted in longer survival.
“KPT-8602 displays better tolerability, [compared with] the first-generation SINE selinexor, allowing for daily dosing and resulting in effective anti-ALL activity in in vivo patient-derived tumor graft models,” the researchers concluded, “[thus] warranting further evaluation of this new drug in patients.” A phase I/II study is underway.
Daelemans D, Neggers JE, De Bie J, et al. KPT-8602 is a second-generation XPO1 inhibitor with improved in vivo tolerability that demonstrates potent acute lymphoblastic leukemia activity. Abstract LB-210. Presented at the AACR Annual Meeting, April 18, 2016; New Orleans, LA.