Читать книгу Successful Drug Discovery, Volume 5 - Группа авторов - Страница 30

A first example is the discovery of vorinostat by Ron Breslow (Columbia University) and Paul Marks (Sloan Kettering). Its story has been told by Ron Breslow in the second volume of this series; he entitled the chapter “From DMSO to the Anticancer Compound SAHA, an Unusual Intellectual Pathway for Drug Design,” which nicely sets the stage [102]. The journey started in 1971 from the observation by Virologist Dr. Charlotte Friend that a highly concentrated dimethyl sulfoxide (DMSO) solution can cause preferential differentiation of suspended murine erythroleukemia cells (MELCs) to red blood cells. This was certainly a stunning observation, but most industrial medicinal chemists would not have taken DMSO as a viable starting point for a drug optimization campaign. The connection between Paul Marks and Ron Breslow occurred as a result of one of Marks' postdocs previously pursuing a fellowship in the Breslow laboratory. When options for starting a compound optimization program were discussed, she brought up the notion of getting in touch with him. Although Ron Breslow was a physical organic chemist by nature, he was immediately intrigued. The discussion started a collaboration that lasted for more than 30 years. Left with a thrilling phenotype, but no idea of a binding protein, nor any useful pharmacophore, optimization was challenging. They set out to test numerous small polar molecules and discovered that introduction of two polar side chains to DMSO led to a significant (∼50‐fold) increase in activity. Also, the team discovered that introduction of hydroxamic acids did improve potency. Recognizing the strong complexing properties of hydroxamic acids, they speculated that metal binding may play an important role. Further optimization led to suberoylanilide hydroxamic acid (SAHA). Structural similarity of SAHA to the natural product trichostatin A led to the assumption that SAHA could also target histone deacetylase (HDAC) [103]. This was confirmed in further studies [104], and zinc chelation turned out to be the key binding motif. SAHA is a pan HDAC inhibitor. Its moderate potency of 2.5 μM represents a good compromise of activity and avoiding toxic side effects (Figure 1.14).

In contrast to Silverman who established collaborations with large pharmaceutical companies directly, Breslow and Marks, together with Richard Rifkind (Memorial Sloan Kettering Cancer Center) and Victoria Richon in 2001, established a dedicated company to progress the compound. The newly founded Aton Pharma Inc. acquired the patent rights from Sloan Kettering and Columbia University. Through venture capital, a phase 1 clinical trial was performed [105], which demonstrated good tolerability and target engagement (histone acetylation in mononuclear cells and tumor tissue obtained through biopsies; pre‐ and post‐treatment was analyzed). Also certain transient antitumor activities were observed in 37 cancer patients suffering either from solid tumors or hematological malignancies. In February 2004, Merck acquired Aton Pharma when SAHA was still in phase 2 clinical trials.

Figure 1.14 Structures of DMSO and hydroxamic acid derivatives leading to the discovery of vorinostat.

Vorinostat was approved in 2006 in the United States for the treatment of relapsed or refractory cutaneous T‐cell lymphoma (CTCL), a rare form of lymphoma. Approval for CTCL was denied in Europe and trials for other indications have not been successful, yet the search for further indications, in particular in combination with other drugs, is still ongoing [106]. Even more importantly, vorinostat (Zolinza™) was the first approved HDAC inhibitor, opening the way to addressing a completely new class of therapeutically exploitable enzymes [107]. Five HDAC inhibitors have been approved by the FDA to date and several other drugs targeting that enzyme class are now in clinical development [108]. The development of the subtype selective HDAC inhibitor chidamide has been reviewed in Chapter 5, Volume 2 of this series [109]. The potential of epigenetics as demonstrated by HDAC inhibitors progressing into clinical development set the basis for a whole new research field and stimulated the formation of powerful public–private consortia like the Structural Genomix consortium. Started in 2004, to date this specific effort resulted in the publication of more than 2200 X‐ray structures and 1700 scientific publications, and more than 75 chemical probes are available for biological studies on request, which tremendously increased the knowledge on the relevant protein families. This had significant impact on our understanding of structural requirements of epigenetic regulation, employing not only erasers like HDACs but also readers like bromo‐ and tudor‐domains and writers like acetyl and methyl transferases.