Discovery of Dinaciclib (SCH 727965): A Potent and Selective Inhibitor of Cyclin-Dependent Kinases

Abstract

Inhibition of cyclin-dependent kinases (CDKs) has emerged as an attractive strategy for the development of novel oncology therapeutics. Herein is described the utilization of an in vivo screening approach with integrated efficacy and tolerability parameters to identify candidate CDK inhibitors with a suitable balance of activity and tolerability. This approach has resulted in the identification of SCH 727965, a potent and selective CDK inhibitor that is currently undergoing clinical evaluation.

Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

“…Additionally, simultaneous addition of SCH 727965 (a potent CDK inhibitor; refs. 15,20) during hydroxyurea exposure also suppressed accumulation of g-H2AX, in a dose-dependent manner (Table 1). Representative fluorescence-activated cell sorter plots stemming from these experiments are shown in Supplementary Fig.…”

“…Experimental compounds A, B, C, D, E, SCH 900776, and SCH 727965 were synthesized and purified as described previously (14)(15)(16)(17). Clinical formulations of gemcitabine and pemetrexed were obtained from Eli Lilly (Gemzar, Alimta, Eli Lilly).…”

Dinaciclib (SCH 727965), a Novel and Potent Cyclin-Dependent Kinase Inhibitor

“…In parallel, MED was defined as the dose, given by the same schedule, associated with >50% tumor growth inhibition. Promising compounds were further profiled in rats and dogs (21). The screening data pertinent to SCH 727965 are outlined in Table 1.…”

“…Selection of Dinaciclib (SCH 727965; Fig. 1A) for clinical development was facilitated by a range of diverse assays and included an in vivo screening strategy that identified candidate compounds with the optimal combination of pharmacokinetic, efficacy, and safety characteristics (21). This highly effective, functional approach allowed for rapid benchmarking against known CDK inhibitors with undesirable side effects, such as flavopiridol (Fig.…”

Synthesis of 3H‐, 13C3‐, and 14C‐labeled Sch 727965

“…Inhibitors of the CDKs can be used to treat diseases such as cancer, which is characterized as uncontrolled cell proliferation, by causing apoptosis. 2 Sch 727965 (1, Figure 1) is a CDK inhibitor 3 that can potentially be used for the treatment of diseases associated with the CDKs, such as cancer. Sch 727965 was labeled with three different isotopes within our group.…”