Paul D. Kemmitt

Discovery of a Potent and Selective EGFR Inhibitor (AZD9291) of Both Sensitizing and T790M Resistance Mutations That Spares the Wild Type Form of the Receptor

Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number of years. Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addition, EGFR wild type receptor inhibition inherent with these agents can lead to dose limiting toxicities of rash and diarrhea. We describe herein the evolution of an early, mutant selective lead to the clinical candidate AZD9291, an irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations with selectivity over the wild type form of the receptor. Following observations of significant tumor inhibition in preclinical models, the clinical candidate was administered clinically to patients with T790M positive EGFR-TKI resistant NSCLC and early efficacy has been observed, accompanied by an encouraging safety profile.

Discovery of a potent, selective, and orally efficacious pyrimidinooxazinyl bicyclooctaneacetic acid diacylglycerol acyltransferase-1 inhibitor.

Inhibition of DGAT-1 is increasingly seen as an attractive mechanism with the potential for treatment of obesity and other elements of the metabolic syndrome. We report here a bicyclooctaneacetic acid derivative in the pyrimidinooxazine structural class of DGAT-1 inhibitors that has good potency, selectivity, and pharmacokinetic characteristics across a variety of species. This compound is an effective inhibitor of DGAT-1 in both intestinal and adipose tissue, which results in a reduction in body weight or body weight gain following oral administration in both mouse and rat models of dietary-induced obesity.

Making medicinal chemistry more effective—application of Lean Sigma to improve processes, speed and quality

The pharmaceutical industry, particularly the small molecule domain, faces unprecedented challenges of escalating costs, high attrition as well as increasing competitive pressure from other companies and from new treatment modes such as biological products. In other industries, process improvement approaches, such as Lean Sigma, have delivered benefits in speed, quality and cost of delivery. Examining the medicinal chemistry contributions to the iterative improvement process of design-make-test-analyse from a Lean Sigma perspective revealed that major improvements could be made. Thus, the cycle times of synthesis, as well as compound analysis and purification, were reduced dramatically. Improvements focused on team, rather than individual, performance. These new ways of working have consequences for staff engagement, goals, rewards and motivation, which are also discussed.

Identification, optimisation and in vivo evaluation of oxadiazole DGAT-1 inhibitors for the treatment of obesity and diabetes

A novel series of DGAT-1 inhibitors was discovered from an oxadiazole amide high throughput screening (HTS) hit. Optimisation of potency and ligand lipophilicity efficiency (LLE) resulted in a carboxylic acid containing clinical candidate 53 (AZD3988), which demonstrated excellent DGAT-1 potency (0.6 nM), good pharmacokinetics and pre-clinical in vivo efficacy that could be rationalised through a PK/PD relationship.

Design and optimization of pyrazinecarboxamide-based inhibitors of diacylglycerol acyltransferase 1 (DGAT1) leading to a clinical candidate dimethylpyrazinecarboxamide phenylcyclohexylacetic acid (AZD7687).

A new series of pyrazinecarboxamide DGAT1 inhibitors was designed to address the need for a candidate drug with good potency, selectivity, and physical and DMPK properties combined with a low predicted dose in man. Rational design and optimization of this series led to the discovery of compound 30 (AZD7687), which met the project objectives for potency, selectivity, in particular over ACAT1, solubility, and preclinical PK profiles. This compound showed the anticipated excellent pharmacokinetic properties in human volunteers.

Discovery of pyrazolo[1,5-a]pyrimidine B-cell lymphoma 6 (BCL6) binders and optimization to high affinity macrocyclic inhibitors

Inhibition of the protein-protein interaction between B-cell lymphoma 6 (BCL6) and corepressors has been implicated as a therapeutic target in diffuse large B-cell lymphoma (DLBCL) cancers and profiling of potent and selective BCL6 inhibitors are critical to test this hypothesis. We identified a pyrazolo[1,5-a]pyrimidine series of BCL6 binders from a fragment screen in parallel with a virtual screen. Using structure-based drug design, binding affinity was increased 100000-fold. This involved displacing crystallographic water, forming new ligand-protein interactions and a macrocyclization to favor the bioactive conformation of the ligands. Optimization for slow off-rate constant kinetics was conducted as well as improving selectivity against an off-target kinase, CK2. Potency in a cellular BCL6 assay was further optimized to afford highly selective probe molecules. Only weak antiproliferative effects were observed across a number of DLBCL lines and a multiple myeloma cell line without a clear relationship to BCL6 potency. As a result, we conclude that the BCL6 hypothesis in DLBCL cancer remains unproven.

Enhanced cytocompatibility and functional group content of poly(L-lysine) dendrimers by grafting with poly(oxazolines)

When considering the design of an advanced drug delivery system, a common desirable attribute is to have a prolonged residence time in blood circulation so that accumulation and localised payload release may occur at the site of interest (e.g. a tumour). Polyethylene glycol (PEG) has been a gold standard for fulfilling this requirement, and consequently has been well investigated as a material for surface modification of dendrimers. As an alternative, we have explored the use of polyoxazolines (POZ)s as materials for modifying the surface of a generation 5 L-lysine dendrimer and found that there was a significant improvement in the biocompatibility properties over the unmodified dendrimer. One particularly useful advantage of POZ over PEG lies in the main-chain pendant groups available that we were able to exploit to impart functionality. Modifying the POZ to have pendant carboxyl groups led to a novel modified dendrimer with significantly more sites for conjugation. With this, we have demonstrated a sixfold increase in the loading of coumarin (our model compound) when compared to a non-functional POZ equivalent.

Optimization of Brain Penetrant 11β-Hydroxysteroid Dehydrogenase Type I Inhibitors and in Vivo Testing in Diet-Induced Obese Mice

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) has been widely considered by the pharmaceutical industry as a target to treat metabolic syndrome in type II diabetics. We hypothesized that central nervous system (CNS) penetration might be required to see efficacy. Starting from a previously reported pyrimidine compound, we removed hydrogen-bond donors to yield 3, which had modest CNS penetration. More significant progress was achieved by changing the core to give 40, which combines good potency and CNS penetration. Compound 40 was dosed to diet-induced obese (DIO) mice and gave excellent target engagement in the liver and high free exposures of drug, both peripherally and in the CNS. However, no body weight reduction or effects on glucose or insulin were observed in this model. Similar data were obtained with a structurally diverse thiazole compound 51. This work casts doubt on the hypothesis that localized tissue modulation of 11β-HSD1 activity alleviates metabolic syndrome.

Identification and optimisation of 7-azaindole PAK1 inhibitors with improved potency and kinase selectivity

A novel series of PAK1 inhibitors was discovered from a kinase directed screen. SAR exploration in the selectivity pocket and solvent tail regions was conducted to understand and optimise PAK1 potency and selectivity against targeted kinases. A liganded PAK1 crystal structure was utilised to guide compound design. Permeability and kinase selectivity impacted the translation of enzyme to cellular PAK1 potency. Compound 36 (AZ-PAK-36) demonstrated improved Gini coefficient, good PAK1 cellular potency and has utility as a tool compound for target validation studies.

Tumour regression and improved gastrointestinal tolerability from controlled release of SN-38 from novel polyoxazoline-modified dendrimers

ABSTRACT Irinotecan is used clinically for the treatment of colorectal cancer; however, its utility is limited by its narrow therapeutic index. We describe the use of a generation 5 l‐lysine dendrimer that has been part‐modified with a polyoxazoline as a drug delivery vehicle for improving the therapeutic index of SN‐38, the active metabolite of irinotecan. By conjugating SN‐38 to the dendrimer via different linker technologies we sought to vary the release rate of the drug to generate diverse pharmacokinetic profiles. Three conjugates with plasma release half‐lives of 2.5 h, 21 h, and 72 h were tested for efficacy and toxicity using a mouse SW620 xenograft model. In this model, the linker with a plasma release half‐life of 21 h achieved sustained SN‐38 exposure in blood, above the target concentration. Control over the release rate of the drug from the linker, combined with prolonged circulation of the dendrimer, enabled administration of an efficacious dose of SN‐38, achieving significant regression of the SW620 tumours. The conjugates with 2.5 and 72 h release half‐lives did not achieve an anti‐tumour effect. Intraperitoneal dosing of the clinically used prodrug irinotecan produces high initial and local concentrations of SN‐38, which are associated with gastrointestinal toxicity. Administration of the 21 h release dendrimer conjugate did not produce a high initial Cmax of SN‐38. Consequently, a marked reduction in gastrointestinal toxicity was observed relative to irinotecan treatment. Additional studies investigating the dose concentrations and dose scheduling showed that a weekly dosing schedule of 4 mg SN‐38/kg was the most efficacious regimen. After 4 doses at weekly intervals, the survival period of the mice extended beyond 70 days following the final dose. These extensive studies have allowed us to identify a linker, dose and dosing regimen for SN‐38 conjugated to polyoxazoline‐modified dendrimer that maximised efficacy and minimised adverse side effects.