The biological profile of PD 0325901: A second generation analog of CI-1040 with improved pharmaceutical potential (2024)

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CI-1040, the first MEK inhibitor to enter clinical evaluation, was advanced into development based on promising preclinical activity. While Phase 1 data pointed to promising hints of clinical activity, efficacy in Phase 2 single agent screening studies was insufficient to warrant continued development. Target suppression in Phase 1 tumor biopsies was < 90% in 8 of 11 tumors tested and the assessment of MEK as a viable drug target remained unconfirmed. The finding that CI-1040 was clinically well tolerated at doses that clearly resulted in significant MEK inhibition provided the impetus to develop more potent MEK-targeted agents with greater systemic exposure. PD0325901 has been identified as a significantly more potent analog of CI-1040 with an improved pharmaceutical profile warranting clinical evaluation. Like CI-1040, PD0325901 is non-competitive with ATP and is exquisitely specific and highly potent against purified MEK, exhibiting a K_i^app of 1 nM against activated MEK1 and MEK2. PD0325901 is roughly 500-fold more potent than CI-1040 with respect to its cellular effects on phosphorylation of ERK1 and ERK2, exhibiting subnanomolar activity. The improved potency of PD0325901 relative to CI-1040 is also evident in vivo. A single oral dose of PD0325901 (25 mg/kg) suppressed phosphorylation of ERK by >50% at 24 hours post-dosing. In comparison, CI-1040 at a much higher dose (150 mg/kg) could only inhibit pERK levels for roughly 8 hours, returning to control levels by 24 hours after treatment. Oral efficacy comparisons revealed that the dose required to produce a 70% incidence of complete tumor responses (C26 model) was 25 mg/kg/day versus 900 mg/kg/day for PD0325901 and CI-1040, respectively. Anticancer activity of PD 0325901 has been demonstrated for a broad spectrum of human tumor xenografts, significantly inhibiting the growth of 6 out of 7 human tumor models tested. PD 0325901 was also shown to be highly efficacious and effective at inhibiting ERK phosphorylation when administered by the IV route. The improved anticancer activity of PD0325901 compared to CI-1040 is likely due to several contributing pharmacological factors, including longer duration and greater potency of MEK inhibition, as well as greater solubility leading to improved bioavailability, and increased metabolic stability. Based on its highly specific inhibition of MEK and its overall pharmaceutical profile, PD0325901 has the potential to provide ultimate validation of MEK as an anticancer drug target. Phase 1 trials with this agent are underway.