6 research outputs found
Development of Highly Potent and Selective Steroidal Inhibitors and Degraders of CDK8
Cortistatin A is a natural product
isolated from the marine sponge
Corticium simplex and was found to be a potent and selective inhibitor
of CDK8. Many synthetic groups have reported total syntheses of Cortistatin
A; however, these syntheses require between 16 and 30 steps and report
between 0.012–2% overall yields, which is not amenable to large-scale
production. Owing to similarities between the complex core of Cortistatin
A and the simple steroid core, we initiated a campaign to design simple,
more easily prepared CDK8 inhibitors based on a steroid scaffold that
would be more convenient for large-scale synthesis. Herein, we report
the discovery and optimization of JH-VIII-49, a potent and selective
inhibitor of CDK8 with a simple steroid core that has an eight-step
synthesis with a 33% overall yield, making it suitable for large-scale
preparation. Using this scaffold, we then developed a bivalent small
molecule degrader, JH-XI-10-02, that can recruit the E3 ligase CRL4<sup>Cereblon</sup> to promote the ubiquitination and proteosomal degradation
of CDK8
Discovery of a benzo[e]pyrimido-[5,4-b][1,4]diazepin-6(11H)-one as a Potent and Selective Inhibitor of Big MAP Kinase 1
Kinome-wide selectivity profiling of a collection of 2-amino-pyrido[2,3-d]pyrimidines followed by cellular structure−activity relationship-guided optimization resulted in the identification of moderately potent and selective inhibitors of BMK1/ERK5 exemplified by <b>11</b>, <b>18</b>, and <b>21</b>. For example, <b>11</b> possesses a dissociation constant (<i>K</i><sub>d</sub>) for BMK1 of 19 nM, a cellular IC<sub>50</sub> for inhibiting epidermal growth factor induced BMK1 autophosphorylation of 0.19 ± 0.04 μM, and an Ambit KINOME<i>scan</i> selectivity score (<i>S</i><sub>5</sub>) of 0.035. Inhibitors <b>18</b> and <b>21</b> are also potent BMK1 inhibitors and possess favorable pharmacokinetic properties which enable their use as pharmacological probes of BMK1-dependent phenomena as well as starting points for further optimization efforts
Discovery of a benzo[e]pyrimido-[5,4-b][1,4]diazepin-6(11H)-one as a Potent and Selective Inhibitor of Big MAP Kinase 1
Kinome-wide selectivity profiling of a collection of 2-amino-pyrido[2,3-d]pyrimidines followed by cellular structure−activity relationship-guided optimization resulted in the identification of moderately potent and selective inhibitors of BMK1/ERK5 exemplified by <b>11</b>, <b>18</b>, and <b>21</b>. For example, <b>11</b> possesses a dissociation constant (<i>K</i><sub>d</sub>) for BMK1 of 19 nM, a cellular IC<sub>50</sub> for inhibiting epidermal growth factor induced BMK1 autophosphorylation of 0.19 ± 0.04 μM, and an Ambit KINOME<i>scan</i> selectivity score (<i>S</i><sub>5</sub>) of 0.035. Inhibitors <b>18</b> and <b>21</b> are also potent BMK1 inhibitors and possess favorable pharmacokinetic properties which enable their use as pharmacological probes of BMK1-dependent phenomena as well as starting points for further optimization efforts
Selective Aurora Kinase Inhibitors Identified Using a Taxol-Induced Checkpoint Sensitivity Screen
The members of the Aurora kinase family play critical
roles in
the regulation of the cell cycle and mitotic spindle assembly and
have been intensively investigated as potential targets for a new
class of anticancer drugs. We describe a new highly potent and selective
class of Aurora kinase inhibitors discovered using a phenotypic cellular
screen. Optimized inhibitors display many of the hallmarks of Aurora
inhibition including endoreduplication, polyploidy, and loss of cell
viability in cancer cells. Structure–activity relationships
with respect to kinome-wide selectivity and guided by an Aurora B
co-crystal structure resulted in the identification of key selectivity
determinants and discovery of a subseries with selectivity toward
Aurora A. A direct comparison of biochemical and cellular profiles
with respect to published Aurora inhibitors including VX-680, AZD1152,
MLN8054, and a pyrimidine-based compound from Genentech demonstrates
that compounds <b>1</b> and <b>3</b> will become valuable
additional pharmacological probes of Aurora-dependent functions
Human Cyclin-dependent kinase 12 (CDK12), kinase domain; A Target Enabling Package
<p>Cyclin-dependent kinase 12 (CDK12) phosphorylates RNA Pol II C-terminal domain (CTD) to promote transcriptional elongation of large DNA damage response genes. CDK12 is frequently mutated or amplified in cancer and its loss sensitises cells to DNA damage. Here we present 3 crystal structures of the human CDK12/CycK complex including apo, AMP-PNP and covalent inhibitor complexes. Kinase assays compare domain truncations and report the Km values for substrate. THZ531 is presented as a potent and selective inhibitor of CDK12 with nanomolar activity in leukemic cell lines.</p
Human Cyclin-dependent kinase 12 (CDK12), kinase domain; A Target Enabling Package
<p>Cyclin-dependent kinase 12 (CDK12) phosphorylates RNA Pol II C-terminal domain (CTD) to promote transcriptional elongation of large DNA damage response genes. CDK12 is frequently mutated or amplified in cancer and its loss sensitises cells to DNA damage. Here we present 3 crystal structures of the human CDK12/CycK complex including apo, AMP-PNP and covalent inhibitor complexes. Kinase assays compare domain truncations and report the Km values for substrate. THZ531 is presented as a potent and selective inhibitor of CDK12 with nanomolar activity in leukemic cell lines.</p