Aphios Corporation

Vitamin D is the general name for a collection of natural sterol-like substances including vitamin D₂ and D₃. Vitamin D₃ is synthesized in the skin from 7-dehydrocholesterol, a cholesterol breakdown product, via photochemical reactions using ultraviolet (UV) radiation from sunlight. The inert vitamin D₃ is first converted to a largely inert intermediate by the liver to 25-HydroxyVitamin D₃ (25-OH-D₃) and then converted by the kidney to the bioactive hormone 1-25-DihydoxyVitamin D₃ (1,25(OH)₂D₃). The bioactive vitamin D hormone, 1,25(OH)₂D₃, mediates its anticancer activity by binding to the vitamin D receptor (VDR) that is principally located in the nuclei of the target cell.

We have utilized the non-toxic intermediate 25-HydroxyVitamin D₃ (25-OH-D₃) to develop a class of novel, non-toxic VDR affinity-binding analogs of 25-OH-D₃. We hypothesized that if we could covalently attach (alkylate) 25-OH-D₃, a non-toxic and biologically inert pre-hormonal form of 1,25(OH)₂D₃, to the hormone-binding pocket of VDR, we might be able to convert the latter into a transcriptionally active form. This would make 25-OH-D₃ biologically active. Furthermore, we might be able to translate the non-toxic nature of 25-OH-D₃ into its VDR-alkylating analog. Thereby harnessing the anticancer property of a ‘1,25(OH)₂D₃-like molecule’ without systemic toxicity.

In this effort, we synthesized VDR–alkylating analogs of the largely inert pre-hormone 25-OH-D₃ [MPI-105 and MPI-106] and the inert vitamin D₃ [MPI-107], and demonstrated that they possess strong anti-tumor activity in a mouse prostate tumor xenograft model without significant toxicity [US Patent Pending].

We have also developed a VDR alkylating derivative of the bioactive hormone identified as MPI-109, 1,25-dihydroxy-vitamin D₃-3-bromoacetate [1,25(OH)₂D₃-3-BE], that covalently links the bioactive hormone 1,25(OH)₂D₃ inside the ligand-binding pocket of the nuclear vitamin D receptor (VDR) [US Patent Pending]. In this case, our hypothesis was that if MPI-109 cross-links to the hormone-binding pocket of VDR, there would be significantly reduced catabolic degradation of this compound. As a result, we might need less of this compound to have an anti-tumor effect with reduced toxicity. We have shown through in vitro studies that MPI-109 is a strong antiproliferative agent in several human prostate cancer cells. Additionally, it induced apoptosis in these cells.

Furthermore, through in vivo studies, we demonstrated that MPI-109 produced strong anti-prostate tumor effect in athymic nude mice with a dose approximately 10 times less than the parent hormone, 1,25(OH)₂D₃ without significant toxicity. Therefore, MPI-109 demonstrated a strong translational potential as a therapeutic agent for prostate cancer.