7LHB

Crystal structure of Bcl-2 in complex with prodrug ABBV-167

Summary for 7LHB

• Entry DOI: 10.2210/pdb7lhb/pdb
• Descriptor: Apoptosis regulator Bcl-2, Phosphoric acid mono-[5-(5-{4-[2-(4-chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-2-{3-nitro-4-[(tetrahydro-pyran-4-ylmethyl)-amino]-benzenesulfonylaminocarbonyl}-phenoxy)-pyrrolo[2,3-b]pyridin-7-ylmethyl] ester (3 entities in total)
• Functional Keywords: bcl-2, apoptosis, prodrug, abbv-167
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 61002.08

Authors

Judge, R.A.,Salem, A.H. (deposition date: 2021-01-21, release date: 2021-04-14, Last modification date: 2023-10-18)

Primary citation

Salem, A.H.,Tao, Z.F.,Bueno, O.F.,Chen, J.,Chen, S.,Edalji, R.,Elmore, S.W.,Fournier, K.M.,Harper, K.C.,Hong, R.,Jenkins, G.J.,Ji, J.,Judge, R.A.,Kalvass, J.C.,Klix, R.C.,Ku, Y.Y.,Leverson, J.D.,Marks, R.A.,Marsh, K.C.,Menon, R.M.,Park, C.H.,Phillips, D.C.,Pu, Y.M.,Rosenberg, S.H.,Sanzgiri, Y.D.,Sheikh, A.Y.,Shi, Y.,Stolarik, D.,Suleiman, A.A.,Wang, X.,Zhang, G.G.Z.,Catron, N.D.,Souers, A.J.
Expanding the Repertoire for "Large Small Molecules": Prodrug ABBV-167 Efficiently Converts to Venetoclax with Reduced Food Effect in Healthy Volunteers.
Mol.Cancer Ther., 20:999-1008, 2021

PubMed Abstract: 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. Although 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 (, 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.

PubMed: 33785651
DOI: 10.1158/1535-7163.MCT-21-0077

Experimental method

X-RAY DIFFRACTION (2.068 Å)