Luck or genius: from DMSO to the cancer drug Volino on his legendary path

Vorinostat is a histone deacetylase (HDAC) inhibitor that interferes with the activity of deacetylase for therapeutic purposes.
October 6, 2006, the U.S. FDA approved Volinotha for the treatment of skin T-cell lymphoma (cutaneous T-cell lymphoma, CTCL).
's research began when researchers stumbled upon the role of dimethyl sulfoxide (DMSO) in inducing cell differentiation in leukemia.
researchers, starting with DMSO, the simplest molecule, successfully developed the first HDAC inhibitor through bold hypothesis and scientific evidence.
study of the inhibition of transflyction of red leukemia cells (murineerthroleukemia cells, MELC) in mice, the Friend team found that about two-thirds of cancer cells in cell cultures containing low concentrations of DMSO turned red.
they speculated that DMSO might stimulate MELC differentiation, which in turn increased hemoglobin concentration and reduced cell deterioration, so the color of cancer cells turned red.
, the researchers used DMSO as the starting point for Volino's research and development.
Figure 1. The discovery of DMSO pilot compounds The Breslow team then carried out corresponding structural relationship studies on DMSO and expanded from DMSO to similar polar compounds, and found that the following compounds 1-12 have similar effects of DMSO induced MELC differentiation.
2. Polar compounds 1-12 Scientists hypothesize that when cells synthesize DNA, these polar compounds may alter the composition of DNA or DNA-protein complexes, causing cells to change during infection and differentiation.
In order to further improve the induced activity of the compound, the researchers designed and synthesized a series of compound 5's dipolars with compound 5 as the starting point, in order to increase its binding ability to unknown targets by increasing the polar group of the compound.
activity determination results show that the simplest diamyl acetyl diamine 13 activity is not stronger than compound 5, but when the chain length between the two polymers increased to 5-8, its activity was significantly enhanced, and at low concentrations also has a higher induction activity.
However, when the chain length is 7-8, it has obvious cytotoxic activity, while when the chain length is 5-6, both have a higher induction activity and do not produce cytotoxic activity, and hexamethylene bisacetamide (HMBA) has the highest induction activity.
screening found that compound 14 was the preferred molecule with a significant difference between activity and toxicity, and was the first milestone compound.
Figure 3. Isohydroxyac acid, a dual-functional base of compounds 13 and 14, Although the target for the role of diamide compounds to induce cell differentiation is still unclear, but previous studies have proved that the two amide groups are the optimal structure of the compound.
So the researchers further speculated that the two alamide groups may have pharmacologically active by chelating with metal ions or forming hydrogen bonds, so the researchers used isohydroxy acid fragments to replace the amylamine base to further enhance the compound's chelation with the metal or increase the chances of hydrogen bond binding, thus synthesized a series of dihydroxy isoic acid compounds.
the effects of flexible connection base, rigidly soft connection base and rigid connection base on activity.
Figure 4. The study of the relationship between the composition of bihydroxyxyacid compounds (1) replacing the amamide base with isohydroxyacid fragments significantly increased the activity of the derivatives, of which the activity of dihydroxyhydroxyacid 16 was the highest, about 100 times that of HMBA; (2) The activity of the bihydroxyhydroxyacids (15 and 17) connecting the base diacids and diacids is lower than that of the compound 16, respectively, and the activity of the connecting base is lower after shortening; (3) the activity disappears after the introduction of methyl (e.g. compounds 18 and 19) in α bits of the acrylic base, which may be related to bit resistance; (4) The activity of toluene isohydroxyxyclic acid 21 is equivalent to that of compound 16, while the activity of isohydroxyhydroxy acid 22 is inactive, and one or three isohydroxy acids are inactive (5) Compounds 23 that are embedded with one medyl on the basis of compound 21 each disappeared, but compound 24 activity of compounds embedded after each two medehyles was restored, but compounds 25 and 26 were significantly increased if dual bonds were introduced.
changes in activity caused by small structural changes, suggesting the precision and complexity of compound-target binding.
researchers further screened the induced differentiation activity of more active derivatives on HL-60 and HT-29 cells, and the results showed that compound 16 had the best activity.
Volino's discovery and approval of the listing because hydroxyic acid is a powerful metal chelating group, but the presence of two powerful chelating groups may not be necessary, so the researchers replaced it with a polar group, synthesized more than 600 compounds.
But in the process of structural transformation, consider replacing hydroxyic acid with non-polar hydrophobic groups, hydrophobic interaction with hydrophobic cavities or fissures at the active site of the enzyme or the subject may be used to enhance activity, resulting in a more active derivative27.
late-stage activity assay found that the inhibitory activity IC50 of derivatives 27 to HDAC1 and HDAC3 reached 1-5 nmol. L-1。
in-body experiments show that derivative 27 has a strong anti-proliferation and apoptosis effect on a variety of tumor cells, and can inhibit the production of blood vessels, and show significant synergy with other anti-tumor drugs.
drug generation dynamics showed that the drug half-life of derivative 27 was 2 hours, and the binding rate with plasma protein was as high as 71%.
was approved by the FDA in 2007 to treat relapsed skin T-cell lymphoma, and Volino was born.
Figure 5. Volinot Volino's advent can be said to have created a miracle, it is in the target and the mechanism of action are not clear, relying entirely on the most traditional relationship research, after a step-by-step exploration of the final listing.
1. Charlotte Friend, William Scher, J. G. Holland, etc. Hemo-globin synthesis inmurine virus-induced leukemic cells in vitro: stimulation of erythroid differentiation by dimethyl sulfoxide. J. PNAS, 1971, 378-382. 2.Paul A. Marks,Richard A. Rifkind,Ronald Breslow, etc. Novel potent inducers of terminal differentiation and methods of use thereof. P. United States, 07/522558, 1992. 3.Richard Campbell, Eric Sanchez, Jeffrey Steinberg, etc. The potent histone deacetylase inhibitor vorinostat, in combination with melphalan, markedly enhances the anti-myeloma effects of chemotherapy in vitro and in vivo. J. Cancer Research, 2008, 12-16.