Venetoclax is a first-in-class, oral, selective BCL-2 inhibitor (BH3-only mimetic). The drug is approved in numerous countries, including those of the EU and in the USA, for the treatment of adults with relapsed or refractory (RR) CLL. The drug arose from research by Abbott Laboratories (now AbbVie) during a collaboration with Genentech and is being codeveloped by AbbVie and Genentech/Roche primarily.
The manufacturing route to venetoclax takes place by
coupling of three key structural subunits: azaindole 162,
sulfonamide 165, and piperazine 172. The first of these
subunits was generated in two steps from commercially
available 4-bromo-2-fluoro-1-iodo-benzene (159).
Grignard formation of iodide 159 (i-PrMgCl) followed by
quenching with Boc2O provided the desired tert-butyl ester 160
without the need for chromatographic purification. Aromatic
substitution of crude 160 with azaindole 161 provided access to
162 in 86% yield after recrystallization from EtOAc/heptane. Sulfonamide 165 was
formed in 91% yield and 99.9% purity via aromatic substitution
of commercially available 163 with amine 164 at 80 °C
? ?Synthesis of the third venetoclax subunit, piperazine amine
hydrochloride salt 172, began with commercial cyclohexanone
166. Vilsmeier-Haack formylation of the
sterically more accessible enol tautomer of 166 delivered vinyl
chloride 167 in quantitative yield. Coupling of this chloride
with commercial aryl boronate 168 gave rise to transient enal
169 in 87% assay yield, which was not isolated. Crude 169 was
then carried into a reductive amination reaction with
commercial N-Boc piperazine (170). Precipitation and
recrystallization from acetonitrile ultimately furnished piperazinyl
alkene 171 in 74% yield from 167. Finally, subunit 172
was obtained via Boc removal with concentrated HCl in IPA at
65 °C and subsequent filtration, conditions that provided a 95%
yield of high purity intermediate 172 (>99.5%).The final approach to venetoclax involved a palladiumcatalyzed
coupling of amine 172 with aryl bromide 162, ester
hydrolysis, and coupling of the resulting carboxylic acid with
sulfonamide 165. In practice, Buchwald-Hartwig amination of 162 with 172 proceeded smoothly and
relied upon workup with cysteine to enable cleansing of
residual palladium from the reaction mixture. This reaction
gave rise to advanced intermediate 173 in 89% yield after
crystallization from cyclohexane. Treatment of 173 with t-
BuOK/H2O/2-MeTHF at 55 °C provided the corresponding
free acid, which was immediately activated with EDC/DMAP/
Et3N to promote coupling with sulfonamide 165 at room
temperature. The final drug target could be accessed by
crystallization from EtOAc and washing with 1:1 DCM/EtOAc,
yielding venetoclax (XVIII) in free base form in 71% over
the two final steps. This synthetic route was capable of
fashioning the drug target in 52% overall yield based on the
longest linear sequence (7 steps).
ChEBI: A member of the class of pyrrolopyridines that is a potent inhibitor of the antiapoptotic protein B-cell lymphoma 2. It is used for treamtment of chronic lymphocytic leukemia with 17p deletion.
Venetoclax displayed cytotoxic activity in various tumour samples/cell lines, including some derived from CLLs, various other NHL subtypes, acute lymphoblastic leukaemias (ALLs), AMLs, chronic myeloid leukaemias (CMLs) and MMs. Notably, the sensitivity of venetoclax correlated with higher BCL-2 expression, with a BCL-2 high status [i.e. BCL-2 gains, BCL-2 amplifications, or the t translocation, which is a notable cause of deregulated BCL-2 expression] and higher BCL-2/MCL-1 ratios being potentially predictive of sensitivity to the drug.
Venetoclax, codeveloped by
AbbVie (previously Abbott Laboratories) and Genentech/
Roche, was approved in the US for treatment of patients with
chronic lymphocytic leukemia (CLL). To meet qualifications
for venetoclax treatment, patients must have received prior
therapy and possess the 17p deletion genetic mutation, as
determined by USFDA testing. Venetoclax functions as a
selective inhibitor of B cell lymphoma subtype 2 (BCL-2),
which is often overexpressed on malignant cells and thus leads
to impairment of the apoptotic pathway. Along these lines,
the orally dosed small molecule drug restores the ability of
malignant cells to undergo apoptosis as its mechanism of
action.90 Although other BCL-2 inhibitors are known, development
of similar agents such as navitoclox have been pursued
and halted due to undesired inhibition of BCL-XL, leading to
significant thrombocytopenia and demonstrating the need for
more selective inhibitors. Venetoclax is also currently being
considered for approval in Europe and Canada for similar
indications and is in various stages of development for the
treatment of non-Hodgkin lymphomas (NHL), acute myeloid
leukemia (AML), multiple myeloma (MM), and several other
disorders, either as a combination therapy or a stand-alone
ABT-199, also known as venetoclax, is a small, oral chemical molecule used for the treatment of chronic lymphocytic leukemia (CLL) associated with a specific chromosomal abnormality. As a second line treatment drug of CLL, ABT-199 take effects through acting as a BH3-mimetic and inhibitor of Bcl-2 (the anti-apoptotic B-cell lymphoma-2protein), further inducing apoptosis of CLL cells but not platelets. It also has the potential for the treatment of ER-positive breast cancer.
Mechanism of action
Venetoclax has high affinity for BCL-2, binding to the protein with an affinity more than three orders of magnitude greater than to BCL-XL or BCL-W in vitro. By binding to BCL-2, the drug displaces BCL-2-bound proapoptotic proteins (such as BIM), resulting in the permeabilization of mitochondrial outer membranes, activation of caspases, and restoration of cancer cell apoptosis, with this process requiring the apoptosis regulators BAX or BAK.
Vogler, M, et al. "ABT-199 selectively inhibits BCL2 but not BCL2L1 and efficiently induces apoptosis of chronic lymphocytic leukaemic cells but not platelets." British Journal of Haematology 163.1(2013):139-42.
Vaillant, Fran?ois, et al. "Targeting BCL-2 with the BH3 Mimetic ABT-199 in Estrogen Receptor-Positive Breast Cancer." Cancer Cell 24.1(2013):120-9.
Lindeman, G. J., et al. "Abstract P2-09-01: Targeting BCL-2 with the BH3 mimetic ABT-199 in ER-positive breast cancer." Cancer Research 73.24 Supplement (2013):P2-09-01-P2-09-01.