Background In search for innovative treatment options we are investigating the highly potent natural compound Disorazol Z as a novel cytotoxic component in a drug-targeting approach for the treatment of LHRH receptor overexpressing cancers. Different Disorazol Z conjugates with D-Lys6-LHRH as LHRH receptor targeting moiety have been subjected to preclinical evaluation. Here we present the selection of the preclinical development candidate AEZS-138 based on in vitro characterization and with respect to PK/PD parameters and provide evidence that LHRH receptor targeting contributes to the mechanism of action.Results Disorazol Z is a potent tubulin binding agent with outstanding cellular cytotoxicity with EC50 values in the subnanomolar range. For all Disorazol Z - D-Lys6-LHRH conjugates, the tubulin binding activity compared to Disorazol Z was either unaltered or just slightly diminished. LHRH receptor binding and activation mediated by the targeting peptide D-Lys6-LHRH was attenuated by conjugation, but still in the low nanomolar EC50 range. The conjugates showed varying cytotoxic activity from low nanomolar to three digit nanomolar EC50values. Comparison in ovarian and endometrium cancer xenograft models revealed potent inhibition of tumor growth for the conjugates, whereas equimolar dosing of Disorazol Z failed to reach statistical significance. PK analysis showed substantial plasma levels for the conjugates with only minor release of Disorazol Z, pointing to stabilization by conjugation and demonstrating reasonable half-life of the intact conjugates as prerequisite for tumor targeting. The tumor models employed have been analysed regarding LHRH-R positivity by mRNA in situ hybridisation.Conclusions All Disorazol Z � D-Lys6-LHRH conjugates analysed so far demonstrate a high potential regarding the treatment of LHRH receptor positive tumors. Based on in vitro characterization and with respect to PK/PD parameters AEZS-138 has been chosen as preclinical development candidate. Preclinical development of AEZS-138 was initiated in Q2/2013.

Cytotoxic conjugates of Disorazol Z with the LHRH receptor agonistic peptide D-Lys<sup>6</sup>-LHRH as approach to targeted therapy of LHRH-R positive tumors

246th National Meeting (2013)

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Cytotoxic conjugates of Disorazol Z with the LHRH receptor agonistic peptide D-Lys6-LHRH as approach to targeted therapy of LHRH-R positive tumors

Cytotoxic conjugates of Disorazol Z with the LHRH receptor agonistic peptide D-Lys⁶-LHRH as approach to targeted therapy of LHRH-R positive tumors