Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12C mutant represents an “Achilles heel” and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket on GDP-bound RAS, locking it in an inactive state. A weak inhibitor at this site was optimized through conformational locking of a piperazine–quinazoline motif and linker modification. Subsequent introduction of a key methyl group to the piperazine resulted in enhancements in potency, permeability, clearance, and reactivity, leading to identification of a potent KRASG12C inhibitor with high selectivity and excellent cross-species pharmacokinetic parameters and in vivo efficacy.

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KRAS is an archetypal high-value intractable oncology drug target. The glycine to cysteine mutation at codon 12 represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 21, AZD4625, a clinical development candidate for the treatment of KRASG12C positive tumors. Highlights include a quinazoline tethering strategy to lock out a bio-relevant binding conformation and an optimization strategy focused on the reduction of extrahepatic clearance mechanisms seen in preclinical species. Crystallographic analysis was also key in helping to rationalize unusual structure–activity relationship in terms of ring size and enantio-preference. AZD4625 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.

Despite the advent of photochemotherapy anthralin remains the routine treatment of chronic plaque psoriasis for most clinicians. This is because many years' experience has shown that anthralin treatment is free of serious side effects. Nevertheless, minor but troublesome side effects have limited its acceptability to patients.In order to examine the pharmacological basis of anthralin irritation we have used a simple technique for establishing the minimal erythemal concentration (MEC) in human skin. METHODCircular glass wells (internal diameter 14 mm and open at both ends) are applied to the upper back of normal adult volunteers. Using different skin sites, a range of concentrations of chromatographically purified anthralin (i,8-dihydroxy-9-anthrone) dissolved in chloroform (volume i ml) is placed in the wells for 60 s. The sites are examined for redness at 24, 48 and 72 h after application. The MEC is defined as the lowest concentration giving visible confiuent erythema corresponding to the circular cross-sectional area of the well. The following concentrations (mg/ioo ml) of anthralin in chloroform were studied: 8,12,20,30,40, and 60. Each experiment included a negative control (chloroform only). In eighteen Caucasian subjects (thirteen female) the mean MEC was 18-4 mg/ioo ml (range 12-30). RESULTS Anthralin erythema in normal skinBoth anthralin in chloroform and chloroform alone produced an immediate erythemal response in most subjects, which lasted up to 10 min. The time course of the delayed erythema response was studied in detail in two normal subjects. In both, delayed erythema appeared at the treated site at 36-48 h after application of anthralin, and was maximal at 48-72 h. The erythema subsided at between 96 and 120 h after application. In all subsequent experiments the MEC was read at 72 h after anthralin application. Anthralin erythema in uninvolved skin of psoriasisThere is evidence to suggest that erythemal responses to phlogistic agents in skin of normal subjects and uninvolved skin of psoriatics may differ (Holti, 1964). Accordingly, the MEC for anthralin was studied on the uninvolved back of six psoriatic patients (one female). The mean MEC for this group 0366-077X/81/0820-0082 S02.00

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