Discovery of VIP236, an αvβ3-Targeted Small-Molecule–Drug Conjugate with Neutrophil Elastase-Mediated Activation of 7-Ethyl Camptothecin Payload for Treatment of Solid Tumors.

Simple Summary: The goal of this work was to improve the tumor selectivity of chemotherapy to reduce side effects and improve efficacy. We designed a drug called VIP236 that delivers chemotherapy directly to tumors due to a specialized "homing feature" that binds to αvβ3 integrins. Solid tumors express high levels of αvβ3 integrins. In contrast, expression of αvβ3 is low in healthy tissues. This difference in expression levels leads to preferential homing of the chemotherapy to tumor cells over healthy tissue to reduce side effects. In human cancer models conducted in mice, VIP236 was shown to substantially accumulate in tumors compared with normal tissue. The high accumulation of VIP236 in the tumors resulted in high and long-lasting tumor regression and reduced metastasis formation in brain and lung in cancer models. The emerging field of small-molecule–drug conjugates (SMDCs) using small-molecule biomarker-targeted compounds for tumor homing may provide new perspectives for targeted delivery. Here, for the first time, we disclose the structure and the synthesis of VIP236, an SMDC designed for the treatment of metastatic solid tumors by targeting αvβ3 integrins and extracellular cleavage of the 7-ethyl camptothecin payload by neutrophil elastase in the tumor microenvironment. Imaging studies in the Lewis lung mouse model using an elastase cleavable quenched substrate showed pronounced elastase activity in the tumor. Pharmacokinetics studies of VIP236 in tumor-bearing mice demonstrated high stability of the SMDC in plasma and high tumor accumulation of the cleaved payload. Studies in bile-duct-cannulated rats showed that biliary excretion of the unmodified conjugate is the primary route of elimination. Treatment- and time-dependent phosphorylation of H2AX, a marker of DNA damage downstream of topoisomerase 1 inhibition, verified the on-target activity of the payload cleaved from VIP236 in vivo. Treatment with VIP236 resulted in long-lasting tumor regression in subcutaneous patient-derived xenograft (PDX) models from patients with non-small-cell lung, colon, and renal cancer as well as in two orthotopic metastatic triple-negative breast cancer PDX models. In these models, a significant reduction of brain and lung metastases also was observed. [ABSTRACT FROM AUTHOR]