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The Company’s interest in cancer pharmaceuticals began with the discovery by its scientists of a cell surface receptor for thyroid hormone and thyroid hormone analogues and the realization that this receptor was a regulator of cancer cell proliferation and of blood vessel proliferation (pathological angiogenesis). The integrin αvβ3 protein bearing the hormone receptor is minimally expressed and not activated on non-dividing, non-malignant cells. The investigative team at the Company found that a thyroid hormone derivative which occurs naturally in human blood, tetraiodothyroacetic acid (tetrac), blocked the actions at the integrin of the latter’s principal ligand, L-thyroxine (T4). Tetrac-derived molecules with high affinity for the thyrointegrin αvβ3 receptors have been shown in preclinical studies to have effective anticancer activity whether T4 is present or not. The anticancer actions include disabling multiple cancer cell survival pathways, inhibiting the process of cancer cell division and systematically removing cancer-related blood vessels.

To focus the actions of tetrac on anticancer activities, the Company chemically modified tetrac to generate compounds with slowed cell entry (and thus prolonged action at the tetrac receptor on the cell surface) and that were unable, once internalized by cells, to enter the cell nucleus. The chemical modifications of tetrac also increased the anticancer potency of the agents produced and desirably expanded the cancer cell gene repertoire that the modified compounds could affect. For example, transcription of the epidermal growth factor receptor (EGFR) gene is downregulated by modified tetrac, as are genes for PD-L1 and PD-1 immune checkpoint proteins and for signaling protein nuclear factor kappa B (NFκB); unmodified tetrac did not affect expression of these genes. It should be noted that each of the products (EGFR, NFκB, PD-L1) of these three genes is acted upon by individual anticancer drugs that are already available in the clinic. Tetrac-based agents also affect the transcription of multiple growth factor genes (see below); what is now available clinically are drugs that affect the actions of single growth factors. We would also point out that cancer cell gene expression is differentially regulated by our lead clinical candidates. That is, most of the disruptive actions of the anticancer compounds developed at NanoPharmaceuticals reflect downregulation of expression of genes that are a part of the natural defenses of cancer cells. In addition, tetrac-based compounds upregulate transcription of certain genes whose products serve to harm tumor cells. These include anti-angiogenic TSP1 and a nuclear inhibitor of beta-catenin, CBY1.

The second aspect of the science of the Company’s compounds involves an attack on blood vessel formation via integrin αvβ3. This integrin via the cell surface thyroid receptor site is a highly specialized regulator on blood vessel cells of adjacent cell surface protein receptors for at least five vascular growth factors. These are VEGF, b-FGF, PDGF, EGF, and IGF-1 as well as other pro-angiogenesis factors. Modified high affinity tetrac molecules at the integrin interrupt via intermolecular crosstalk the binding of all of these vascular growth factors to their own receptors near the integrin.

Finally, tetrac-based molecules block cancer cell repair of double-strand DNA breaks induced by radiotherapy in preclinical models. This enhances the effectiveness of radiotherapy where aggressive DNA repair is an inherent asset of cancer cells.