7lhb

Publication Abstract from PubMed

Since gaining approval for the treatment of chronic lymphocytic leukemia (CLL), the BCL-2 inhibitor venetoclax has transformed the treatment of this and other blood-related cancers. Reflecting the large and hydrophobic BH3-binding groove within BCL-2, venetoclax has significantly higher molecular weight and lipophilicity than most orally administered drugs, along with negligible water solubility. While a technology-enabled formulation successfully achieves oral absorption in humans, venetoclax tablets have limited drug loading and therefore can present a substantial pill burden for patients in high-dose indications. We therefore generated a phosphate prodrug (3, ABBV-167) that confers significantly increased water solubility to venetoclax and, upon oral administration to healthy volunteers either as a solution or high drug-load immediate release tablet, extensively converts to the parent drug. Additionally, ABBV-167 demonstrated a lower food effect with respect to venetoclax tablets. These data indicate that beyond-rule-of-5 molecules can be successfully delivered to humans via a solubility-enhancing prodrug moiety to afford robust exposures of the parent drug following oral dosing.

Expanding the repertoire for "large small molecules" : Prodrug ABBV-167 efficiently converts to venetoclax with reduced food effect in healthy volunteers.,Salem AH, Tao ZF, Bueno OF, Chen J, Chen S, Edalji R, Elmore SW, Fournier KM, Harper KC, Hong R, Jenkins GJ, Ji J, Judge RA, Kalvass JC, Klix RC, Ku YY, Leverson JD, Marks RA, Marsh KC, Menon RM, Park CH, Phillips DC, Pu YM, Rosenberg SH, Sanzgiri YD, Sheikh AY, Shi Y, Stolarik D, Suleiman AA, Wang X, Zhang GGZ, Catron ND, Souers AJ Mol Cancer Ther. 2021 Mar 30. pii: 1535-7163.MCT-21-0077. doi:, 10.1158/1535-7163.MCT-21-0077. PMID:33785651^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.