Maria-Elena Theoclitou

Kinesin motor proteins as targets for cancer therapy

The process of mitosis is a validated point of intervention in cancer therapy and a variety of anti-mitotic drugs are successfully being used in the clinic. To date, all approved antimitotics target the spindle microtubules, thus interfering with spindle dynamics, leading to mitotic arrest and apoptosis. While effective, these drugs are also associated with a variety of side effects, including neurotoxicity. In recent years, mitotic kinesins have attracted significant attention in the search for novel, alternative mitotic drug targets. Due to their specific function in mitosis, targeting these proteins creates an opportunity for the development of more selective antimitotics with an improved side effect profile. In addition, kinesin inhibitors may overcome resistance to microtubule targeting drugs. Drug discovery efforts in this area have initially focused on the plus-end directed kinesin spindle protein (KSP) and a variety of compounds are currently undergoing clinical testing.

Discovery of (+)-N-(3-aminopropyl)-N-[1-(5-benzyl-3-methyl-4-oxo-[1,2]thiazolo[5,4-d]pyrimidin-6-yl)-2-methylpropyl]-4-methylbenzamide (AZD4877), a kinesin spindle protein inhibitor and potential anticancer agent.

Structure-activity relationship analysis identified (+)-N-(3-aminopropyl)-N-[1-(5-benzyl-3-methyl-4-oxo-[1,2]thiazolo[5,4-d]pyrimidin-6-yl)-2-methylpropyl]-4-methylbenzamide (AZD4877), from a series of novel kinesin spindle protein (KSP) inhibitors, as exhibiting both excellent biochemical potency and pharmaceutical properties suitable for clinical development. The selected compound arrested cells in mitosis leading to the formation of the monopolar spindle phenotype characteristic of KSP inhibition and induction of cellular death. A favorable pharmacokinetic profile and notable in vivo efficacy supported the selection of this compound as a clinical candidate for the treatment of cancer.

Identification of 3-amido-4-anilinoquinolines as potent and selective inhibitors of CSF-1R kinase.

3-amido-4-anilinoquinolines are potent and highly selective inhibitors of CSF-1R. Their synthesis and SAR is reported, along with initial efforts to optimize the physical properties and PK through modifications at the quinoline 6- and 7-positions.

Abstract 3912: The discovery of AZD4547: An orally bioavailable, potent and selective N-(5-Pyrazolyl)benzamide FGFR1-3 inhibitor

There is increasing evidence that FGFR signaling plays an important role within human cancer, with members of FGFR family acting as driving oncogenes in a significant number of human tumors. Deregulation of FGFR-signaling has been documented within clinical samples of breast multiple myeloma, bladder, endometrial, gastric, squamous NSCLC and prostate cancers. This dysregulation most frequently occurs through gene amplification, or through genetically altered forms of FGFR proteins. This increasing body of evidence implicating FGFR signaling in cancer has provided rationale for the identification and testing of selective inhibitors of FGFR signaling in the clinic. In this presentation, we describe the progress of our FGFR tyrosine kinase inhibitor programme and report the discovery of N-(5-pyrazolyl)benzamide FGFR inhibitors. Early compounds in this series suffered from poor in vivo pharmacokinetic (PK) properties. The key site of metabolism was identified to be at a basic N-methyl group. This group was shown to be located in the solvent channel of the ATP binding site on binding to FGFR1, and modification could be made without causing major changes to intrinsic binding affinity. However, the first compounds identified with low metabolic clearance also showed a significant reduction in oral bioavailability, due to apparent low permeability and increased efflux potential. The characterization of these PK issues and the discovery of compounds which overcame them, through modulation of pKa, lipophilicity and masking of the polar groups, will be described. Leading compounds showed significant anti-tumor activity in xenograft tumors grown in mice. Detailed characterization of these compounds led to the identification of AZD4547, a potent and selective FGFR tyrosine kinase inhibitor currently in Phase I clinical studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3912. doi:1538-7445.AM2012-3912