Purpose: The catalytic function of BUB1 is required for chromosome arm resolution and positioning of the chromosomal passenger complex for resolution of spindle attachment errors and plays only a minor role in spindle assembly checkpoint activation. Here, we present the identification and preclinical pharmacologic profile of the first BUB1 kinase inhibitor with good bioavailability.Experimental Design: The Bayer compound library was screened for BUB1 kinase inhibitors and medicinal chemistry efforts to improve target affinity and physicochemical and pharmacokinetic parameters resulting in the identification of BAY 1816032 were performed. BAY 1816032 was characterized for kinase selectivity, inhibition of BUB1 signaling, and inhibition of tumor cell proliferation alone and in combination with taxanes, ATR, and PARP inhibitors. Effects on tumor growth in vivo were evaluated using human triple-negative breast xenograft models.Results: The highly selective compound BAY 1816032 showed long target residence time and induced chromosome mis-segregation upon combination with low concentrations of paclitaxel. It was synergistic or additive in combination with paclitaxel or docetaxel, as well as with ATR or PARP inhibitors in cellular assays. Tumor xenograft studies demonstrated a strong and statistically significant reduction of tumor size and excellent tolerability upon combination of BAY 1816032 with paclitaxel or olaparib as compared with the respective monotherapies.Conclusions: Our findings suggest clinical proof-of-concept studies evaluating BAY 1816032 in combination with taxanes or PARP inhibitors to enhance their efficacy and potentially overcome resistance.NOTE: Values represent the mean of at least two independent experiments with two technical replicates. In cases where SDs are not indicated, a single experiment with three or more replicates was conducted. Experimental details to the methods used are given in the Materials and Methods section. Siemeister et al. NOTE: CI 50 interpretation code: CI 50 < 0.8, synergism; 0.8 CI 50 1.2, additivity; CI 50 > 1.2, antagonism. Calculated combination indices for 50% inhibition (CI 50 ) from proliferation assays of cell lines treated with drug combinations as indicated. Monotreatment IC 50 values and the concentrations required in combination of the two test compounds to achieve the CI 50 are shown. All concentrations are given in mol/L.
Bromodomains
(BD) are readers of lysine acetylation marks present
in numerous proteins associated with chromatin. Here we describe a
dual inhibitor of the bromodomain and PHD finger (BRPF) family member
BRPF2 and the TATA box binding protein-associated factors TAF1 and
TAF1L. These proteins are found in large chromatin complexes and play
important roles in transcription regulation. The substituted benzoisoquinolinedione
series was identified by high-throughput screening, and subsequent
structure–activity relationship optimization allowed generation
of low nanomolar BRPF2 BD inhibitors with strong selectivity against
BRPF1 and BRPF3 BDs. In addition, a strong inhibition of TAF1/TAF1L
BD2 was measured for most derivatives. The best compound of the series
was BAY-299, which is a very potent, dual inhibitor with an IC50 of 67 nM for BRPF2 BD, 8 nM for TAF1 BD2, and 106 nM for
TAF1L BD2. Importantly, no activity was measured for BRD4 BDs. Furthermore,
cellular activity was evidenced using a BRPF2– or TAF1–histone
H3.3 or H4 interaction assay.
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