EP-4285998-B1 - GLYCOLIPIDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR USE IN THERAPY

Inventors

• BOTLEY, Andrew
• HAYES, CHRISTOPHER
• SEYMOUR, GRAHAM
• Grabawska, Anna
• CLARKE, PHILIP

Dates

Publication Date

20260506

Application Date

20150407

Claims (5)

1. A compound having the structure or a pharmaceutically acceptable salt thereof, for use in medicine.
2. The compound for use of claim 1, wherein the use is in the treatment of a disease or condition selected from the group comprising cancer, autistic spectrum disorders, Alzheimer's disease, Parkinson's disease, Huntingdon's disease, muscle wasting and viral infection.
3. A pharmaceutical composition comprising a compound having the structure or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, diluent or excipient.
4. The pharmaceutical composition according to claim 3, wherein the composition further comprises at least one further anti-cancer agent.
5. A nutraceutical composition comprising a compound having the structure or a pharmaceutically acceptable salt thereof, together with a nutraceutically acceptable carrier, diluent or excipient.

Description

The present invention relates to a compound as defined in the claims for use as one or more of an antiproliferative agent, a chemotherapeutic agent, an adjuvant, and antiviral agent and a cell sensitising agent. Preferably the compound is an inhibitor of protein translation. The disruption of one or more steps in the control of protein synthesis has been associated with alterations in the cell cycle and/or regulation of cell growth. Evidence supports the concept that some translation factors are proto-oncogenes and proteins involved in translation pathways can act as key regulators of malignant progression (Hershey et al, 2000 Translational Control and Cancer, Cold Spring Harbor Laboratory Press, Cold Spring Harbor). Cancer cells generally show higher rates of protein synthesis compared to normal cells. Accordingly, deregulation of protein synthesis is emerging as a major contributor to cancer progression. Over expression of certain translation factors can lead to malignant transformation and many of the components of the translation pathways are over-expressed in cancer. A number of clinically relevant in-vivo experiments have demonstrated that inhibition of translation may be relevant for the treatment of a range of cancer types e.g. adult T-cell leukaemia, lung, breast and cervical cancer. The requirement for elevated levels of protein synthesis is a common feature of cancer cell growth; therefore it is highly likely that a wider broad spectrum of cancer types will also be amenable to treatment with this class of inhibitor. Inhibitors of translation have shown remarkable promise for use as an adjuvant therapy in combination with chemotherapeutics such as Doxorubicin™. Rapidly proliferating tumour types such as MCF-7 breast cancer cells require relatively more protein synthesis than slower growing cancer cells such as A549 lung carcinoma cells. These slow-growing cancer cell types have relatively higher patient mortality rates five years after diagnosis due to chemoresistance to common in clinic chemotherapeutics agents such as Cisplatin™. Research has shown that cell types such as A549 lung carcinoma or SKOV3 ovarian cancer cells derive resistance to platinum based therapies through the aberrant translation of specific proteins e.g. LARP1. Experimental evidence also suggests that endogenous inhibitors of protein synthesis such as programme cell death 4 (PDCD4) modulate sensitivity to Cisplatin™ and that the levels of these endogenous inhibitors significantly correlate with disease-free survival of ovarian cancer patients. Therapeutic modulation of protein translation by inhibition of the eIF4A RNA helicase' is a proven target for the treatment for a broad range of cancer types. Regulation of protein synthesis at the level of translation initiation (eIF4F complex containing eIF4A) is particularly important in cancer cell growth because they are metabolically highly active. This rapid growth places a heavy demand on the protein synthesis machinery. Additionally cancer cells often produce proteins that provide resistance to commonly used chemotherapeutic drugs and this resistance is determined by selective translation of key proteins i.e. dependant on eIF4A. De novo or acquired resistance to platinum chemotherapy is the leading cause of death in some cancers e.g. Ovarian, and high impact research identifies that this chemo-resistance is due to the aberrant translation of key proteins (e.g. Boussemart et al 2014, Nature, ahead of print doi:10.1038/nature13572; Wolf et al. 2014 Nature, ahead of print doi:10.1038/nature13485); also see reviews by Blagden and Willis, 2011 Nature Oncology Reviews, 8:280-291; Bitterman and Polunovsky 2012, Molecular Cancer Theraputics, 11: 1051-1061). The therapeutic modulation of mRNA translation; inhibition of eIF4A is therefore an excellent and well published intervention point for the treatment of a range of different cancer types; enabling a selective treatment targeted to the biology of the cancer cell. Initiation of translation is a point of convergence for multiple aberrant signalling cascades, and represents a logical approach for targeting chemotherapy-resistant cancer cells (cancer types include but are not limited to ovarian, lung, breast, leukaemia, pancreatic, kidney). There is now compelling evidence that aberrant control of protein synthesis is linked to the progression of a range of other conditions and illnesses. Chronic conditions such as muscle wasting, autistic spectrum disorders, Alzheimer's disease, Huntingdon's disease and Parkinson's disease all share similar patterns of deregulation of protein synthesis and a number of research studies conclude that pharmacological agents targeting the protein synthesis machinery are one potential route to treatment for such conditions. Further experimental evidence also indicates that inhibitors of translation or compounds which act to modify or alter protein synthesis present an attractive opportunity as broad acting a