Abstract
Venetoclax is an orally bioavailable, B-cell lymphoma-2 selective inhibitor used for the treatment of chronic lymphocytic leukemia, small lymphocytic lymphoma, and acute myeloid leukemia. Venetoclax’s crystal structure was until now determined only when it was bound to a B-cell lymphoma-2 (BCL-2) protein, while the crystal structure of this active pharmaceutical ingredient alone has not been reported yet. Herein, we present the first successful crystallization, which provided crystals of venetoclax suitable for X-ray diffraction analysis. The crystal structure of venetoclax hydrate was successfully determined. The asymmetric unit is composed of two crystallographically independent molecules of venetoclax and two molecules of interstitial water. Intramolecular N–H⋯O hydrogen bonding is present in both molecules, and a molecular overlay shows differences in their molecular conformations, which is also observed in respect to venetoclax molecules from known crystal structures of BCL-2:venetoclax complexes. A supramolecular structure is achieved through various N–H⋯N, O–H⋯O, C–H⋯O, C–H⋯π, C–Cl⋯π, ONO⋯π, and π⋯π interactions. The obtained crystals were additionally characterized with spectroscopic techniques, such as IR and Raman, as well as with thermal analysis.
Highlights
The B-cell lymphoma-2 (BCL-2) family of proteins, consisting of three distinctive protein groups, regulate cell death through their direct binding interactions triggering a mitochondrial apoptotic pathway that results in caspase activation and apoptosis [1–16]
We provide detai successful preparation of crystals of venetoclax suitable for single crystal X-ray di analysis, the first crystal structure of venetoclax’s hydrate form, and conformation ysis of its small molecule crystal structure in comparison with the v2eonfe16toclax b BCL-2
In our previous studies on the stability and liquid chromatography analytical method development for venetoclax, we observed that venetoclax formed crystals after a few days from some of the solvents used for the dissolution of venetoclax [59,60]
Summary
The B-cell lymphoma-2 (BCL-2) family of proteins, consisting of three distinctive protein groups (anti-apoptotic proteins, pro-apoptotic effectors, and pro-apoptotic initiators/sensitizers), regulate cell death through their direct binding interactions triggering a mitochondrial apoptotic pathway that results in caspase activation and apoptosis [1–16]. BCL-2 anti-apoptotic family members play a key role in cancer cell survival as well as in drug resistance [17–22]. They are primary inhibition targets for the treatment of several cancers as their inhibition restores the apoptotic ability of malignant cells [23–27]. Venetoclax (Figure 1) is an orally bioavailable, B-cell lymphoma-2 (BCL-2) selective inhibitor and the first-in-class oral BCL-2 inhibitor for the treatment of lymphoid malignancies [28–35]. Venetoclax was first approved by the FDA in 2016 for the treatment of patients with chronic lymphocytic leukemia (CLL) and later for small lymphocytic lymphoma (SLL) and for the treatment of newly diagnosed acute myeloid leukemia (AML) in combination with azacitidine, decitabine, or low-dose cytarabine [36–39]. There are many ongoing clinical trials involving venetoclax in various combination therapies [40], which puts venetoclax on the list of highly valuable drugs
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