# CDK8/19 inhibitors for therapy of advanced prostate cancer

> **NIH NIH R44** · SENEX BIOTECHNOLOGY, INC. · 2021 · $846,340

## Abstract

The growth of most prostate cancers is driven by androgen receptor (AR), a transcriptional regulator that has
both tumor-promoting and tumor-suppressive activities. Aggressive prostate cancer is treated through androgen
deprivation therapy but eventually progresses to castration-refractory prostate cancer (CRPC), which is currently
incurable. Potent AR antagonists and agents that inhibit androgen production eventually fail, as CRPC becomes
androgen-independent, often due to the expression of constitutively active AR variants, notably AR-V7. New AR
antagonists under development cause the degradation of AR and its androgen-independent variants but AR has
not only a tumor-promoting but also a tumor-suppressive activity that will be abrogated by such drugs. Hence,
novel classes of drugs that would be effective against androgen-independent CRPC are urgently needed.
Towards this goal, we are targeting “twin” kinases CDK8 and CDK19, which regulate transcriptional
reprogramming, a key process required for cancer drug resistance and metastasis. CDK8 and CDK19
expression in clinical prostate cancers is strongly associated with CRPC and treatment failure. Senex
Biotechnology has developed the first selective CDK8/19 inhibitors; the most recently identified lead compound
shows excellent in vivo potency and pharmacokinetics. CDK8/19 inhibitors induce no apparent toxicity upon
prolonged administration and show beneficial activities in different cancers, including growth inhibition of
metastatic tumors. CDK8/19 inhibitors, when combined with anti-androgen therapy, suppress CRPC growth in
vivo, with the strongest effect observed in an AR-V7 expressing CRPC model. The combinatorial effect of
CDK8/19 inhibition and anti-androgen therapy is associated with changes in gene expression both in the tumor
and in the stroma. The goals of the proposed Phase II SBIR program are to identify molecular characteristics of
CRPC that make them susceptible to CDK8/19 inhibition, to determine if CDK8/19 inhibitors are effective against
CRPC growing at metastatic sites, and to optimize the formulation of the lead CDK8/19 inhibitor. To achieve
these goals, we will screen a panel of cell-line based and patient-derived xenograft CRPC models for in vivo
response to CDK8/19 inhibition combined with castration or enzalutamide. The observed responses will be
correlated with the tumor genomics and gene expression before and after treatment, to identify molecular
determinants of sensitivity to CDK8/19 inhibitor combined with anti-androgen therapy. We will also evaluate the
effects of the lead CDK8/19 inhibitor on CRPC growth and metastatic spread after orthotopic implantation and
on CRPC growth in the bone, the primary metastatic site in the clinic. Concurrently, we will optimize the
formulation of the lead CDK8/19 inhibitor candidate to achieve the best pharmacokinetics. Upon completion of
this program, the CDK8/19 inhibitor drug candidate will be ready for IND-enabling studies, and the ge...

## Key facts

- **NIH application ID:** 10163807
- **Project number:** 5R44CA203184-03
- **Recipient organization:** SENEX BIOTECHNOLOGY, INC.
- **Principal Investigator:** Mengqian Chen
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $846,340
- **Award type:** 5
- **Project period:** 2015-09-23 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10163807

## Citation

> US National Institutes of Health, RePORTER application 10163807, CDK8/19 inhibitors for therapy of advanced prostate cancer (5R44CA203184-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10163807. Licensed CC0.

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