Transcription associated cyclin-dependent kinases as therapeutic targets for prostate cancer

Abstract

Transcriptional deregulation has emerged as a hallmark of several cancer types. In metastatic castration-resistant prostate cancer, a stage in which systemic androgen deprivation therapies fail to show clinical benefit, transcriptional addiction to the androgen receptor is maintained in most patients. This has led to increased efforts to find novel therapies that prevent oncogenic transactivation of the androgen receptor. In this context, a group of druggable protein kinases, known as transcription associated cyclin-dependent kinases (tCDKs), show great potential as therapeutic targets. Despite initial reservations about targeting tCDKs due to their ubiquitous and prerequisite nature, preclinical studies showed that selectively inhibiting such kinases could provide sufficient therapeutic window to exert antitumour effects in the absence of systemic toxicity. As a result, several highly specific inhibitors are currently being trialled in solid tumours, including prostate cancer. This article summarises the roles of tCDKs in regulating gene transcription and highlights rationales for their targeting in prostate cancer. It provides an overview of the most recent developments in this therapeutic area, including the most recent clinical advances, and discusses the utility of tCDK inhibitors in combination with established cancer agents.

Addressing Transcriptional Dysregulation in Cancer through CDK9 Inhibition

“…Early attempts to inhibit CDK9 induced loss of fitness in normal as well as cancer cells because of its essentiality across multiple lineages . This on-target toxicity was further compounded by the combination of inadequate pharmacokinetics, target selectivity, and/or efficacy displayed by the first generation of CDK9 inhibitors. ,,, Notably, these CDK9 inhibitors had high affinity for other cyclin-dependent kinases. Engineering selectivity for kinases can often prove challenging given the conservative nature of the ATP binding cleft, a critical region for many kinase-directed drugs.…”

“…Direct inhibition of these transcription factors has long been the focus of many drug development and design efforts against cancer . However, this task remains largely elusive due to their lack of established ligandable pockets and large protein–protein interaction interfaces. , One strategy for addressing these inherent challenges is to target druggable proteins that regulate the activation or stability of transcription factors driving a particular disease. , …”

“… 1 , 4 One strategy for addressing these inherent challenges is to target druggable proteins that regulate the activation or stability of transcription factors driving a particular disease. 10 , 11 …”

“… 10 , 12 Broadly, they are primarily known for their phosphorylation of residues at the carboxy-terminal domain of RNA Pol II to drive the initiation, elongation, and termination of transcription. 10 , 13 Moreover, they are often involved in regulating the activation, recruitment, and stability of the transcription factors with which they interact. 10 , 13 , 14 Unlike DNA-binding transcription factors, tCDKs are structurally amenable to pharmacological perturbation.…”

“… 10 , 13 Moreover, they are often involved in regulating the activation, recruitment, and stability of the transcription factors with which they interact. 10 , 13 , 14 Unlike DNA-binding transcription factors, tCDKs are structurally amenable to pharmacological perturbation. Although drug candidates primarily targeting tCDKs are yet to receive FDA approval, the general kinase target class boasts a large share of approved therapies.…”