pd-166285 and Neoplasms

Personalized medicine and therapies represent the goal of modern medicine, as drug discovery strives to move away from one-cure-for-all and makes use of the various targets and biomarkers within differing disease areas. This approach, especially in oncology, is often undermined when the cells make use of alternative survival pathways. As such, acquired resistance is unfortunately common. In order to combat this phenomenon, synthetic lethality is being investigated, making use of existing genetic fragilities within the cancer cell. This Perspective highlights exciting targets within synthetic lethality, (PARP, ATR, ATM, DNA-PKcs, WEE1, CDK12, RAD51, RAD52, and PD-1) and discusses the medicinal chemistry programs being used to interrogate them, the challenges these programs face, and what the future holds for this promising field.

Topics: Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins; Cyclin-Dependent Kinases; DNA-Activated Protein Kinase; Genes, BRCA2; Humans; Neoplasms; Poly(ADP-ribose) Polymerases; Precision Medicine; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Rad51 Recombinase; Synthetic Lethal Mutations

Inducing DNA damage is a well known strategy for attacking cancer, already being used for many years by the application of a variety of anti cancer drugs. Tumor cells and other rapidly dividing cells are more sensitive to DNA damage caused by DNA damaging agents compared to normal cells. While normal cells can rely on various mechanisms for DNA repair in order to protect the integrity of the genome and to promote cell survival, most tumor cells, due to genetic changes, are more challenged when it comes to repair of DNA damage. Wee 1 is a tyrosine kinase that phosphorylates CDC2 at Tyr 15 and as such plays a pivotal role in the G2 DNA damage checkpoint. The strategy of inhibition of Wee 1 by a tyrosine kinase inhibitor is exploiting the impaired options for DNA damage repair especially in cells with deregulated p53, which results in malfunction of the G1 checkpoint. Tumor cells that are unable to rely on the G1 checkpoint are more sensitive to G2 checkpoint abrogation. Administration of DNA damaging chemotherapy in combination with a Wee 1 inhibitor may therefore selectively sensitize p53 deficient cells, while normal cells are spared from toxicity. PD-166285 has been described as a novel G2 abrogator and Wee 1 inhibitor, but has also been characterized as a broad-spectrum receptor tyrosine kinase inhibitor. MK-1775 is a specific and potent inhibitor of Wee-1 and is currently under investigation in a multi-center phase I study in combination with either gemcitabine, carboplatin or cisplatin in patients with advanced solid tumors. Preliminary results show good tolerability and promising anti-cancer activity.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Cycle Proteins; DNA Damage; Drug Screening Assays, Antitumor; G2 Phase; Humans; Neoplasms; Nuclear Proteins; Phosphorylation; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyridones; Pyrimidines; Pyrimidinones; Tumor Suppressor Protein p53