Clinical Trials of Mitotic Kinesin Inhibitors

Activation of STAT3 through combined SRC and EGFR signaling drives resistance to a mitotic kinesin inhibitor in glioblastoma

“…An alternative approach would be to target mitotic kinesins, molecular motor proteins that use microtubules to organize the mitotic spindle. An extensive array of inhibitors against one of these, the mitotic kinesin Kif11, has been developed, and as expected, they are not neurotoxic (Rath and Kozielski, 2012;Rosenfeld, 2015). Furthermore, we have shown that one of them, ispinesib, is highly CNS penetrant and prolongs survival in murine GBM models (Gampa et al, 2020;Venere et al, 2015).…”

“…This has led to development of >50 small-molecule inhibitors of one of these, Kif11, which is involved in formation of the bipolar mitotic spindle. Although phase I and II trials have demonstrated acceptable toxicity of these inhibitors, their clinical efficacy has been disappointing (Chandrasekaran et al, 2015;Rosenfeld, 2015), reflecting drug resistance. Nevertheless, several developments have renewed interest in mitotic kinesin inhibitors, particularly for CNS malignancies.…”

“…Unfortunately, clinical trials of Kif11 inhibitors in hematologic and solid malignancies have been disappointing (Rath and Kozielski, 2012;Rosenfeld, 2015). These drugs are only effective against cells in the G 2 M phase of the cell cycle, and since most of them have a short half-life, the probability of a drug affecting a tumor cell when it is vulnerable is low (Komlodi-Pasztor et al, 2012).…”

Eg5 targeting agents: From new anti-mitotic based inhibitor discovery to cancer therapy and resistance

“…The low therapeutic index of the tested Eg5 inhibitors, such ispinesib, SB-743921, AZD-4877, and MK-0731 is not due to lack of target engagement since the inhibitors target normal cell proliferation leading to neutropenia. However, taking into account the pharmacokinetic data derived from the phase I clinical trials of the compounds tested, one determining factor of success might be the elimination half-live of each compound [115]. As shown in Table 1, the elimination half-lives of ispinesib, SB-743921, AZD-4877, and MK-0731 are all <30 h, whereas the corresponding halflife of ARRY-520 was found to be >90 h. Therefore, the longer half-life of Arry-520 compared to other Eg5 may be one of the reason for the better therapeutic index of Arry-520.…”