A promising strategy for treating triple-negative breast cancer and glioblastoma
Indolinone derivatives inhibit MELK, an enzyme linked to cancer cell cycle regulation, proliferation, and apoptosis. These inhibitors show promise in treating cancers like triple-negative breast cancer and glioblastoma by selectively targeting MELK, reducing cancer cell viability and proliferation.
Background
Maternal embryonic leucine zipper kinase (MELK) has been identified as a significant player in various cellular processes such as cell cycle regulation, proliferation, apoptosis, and RNA processing. Despite being dispensable in normal differentiated adult cells, MELK is crucial for the proliferation of progenitor cells and is highly expressed in several aggressive cancers, including glioblastoma multiforme (GBM) and triple-negative breast cancer (TNBC). Elevated MELK levels correlate with poor prognosis and aggressive disease progression, making it an attractive target for cancer therapy.
However, the development of selective MELK inhibitors has been challenging. Existing kinase inhibitors often lack specificity and can affect multiple targets, leading to off-target effects and reduced therapeutic efficacy. Additionally, the redundancy of MELK functions in non-cancerous cells complicates the identification of selective inhibitors that can effectively target cancer cells without affecting normal cells. The discovery of potent and selective MELK inhibitors remains a critical need to advance targeted therapies for aggressive cancers like TNBC.
Technology overview
The technology involves the development of indolinone compounds which are specifically designed to bind and inhibit MELK. The invention includes detailed chemical structures of these indolinone derivatives, with specific functional groups at the fifth and sixth positions of the indolinone ring that enhance their binding affinity and selectivity towards MELK. The compounds are synthesized through a series of chemical reactions, including acylation, condensation, and hydrolysis, to produce derivatives with varying substituents such as carboxylic acids, esters, amides, and alkoxy groups. These derivatives have been shown to exhibit subnanomolar inhibition constants, making them highly potent inhibitors of MELK. Additionally, the invention provides methods for using these compounds in the treatment or prevention of cancers, particularly TNBC and GBM. The compounds have demonstrated selective inhibition of MELK in cancer cell lines, reducing cancer cell viability and proliferation, thereby highlighting their potential as therapeutic agents.
The technology differentiates itself through its highly specific targeting and potent inhibition of MELK, which is overexpressed in aggressive cancers such as TNBC and GBM. Unlike other members of the AMPK-RK family, MELK is unique in its autoactivation through phosphorylation of its conserved activation loop threonine, making it a distinct target for therapeutic intervention. The indolinone derivatives developed for MELK inhibition demonstrate superior binding affinity due to their structural modifications, particularly the functional groups at the fifth and sixth positions of the indolinone ring. These modifications allow for deeper penetration into the MELK binding site and stronger hydrogen bonding interactions, which are critical for maintaining potency. The selective inhibition of MELK by these compounds in cancer cell lines, without affecting normal cells, highlights the potential for these inhibitors to be used as targeted cancer therapies with minimal off-target effects. This specificity and potency make the indolinone derivatives a promising class of compounds for further development in the treatment of aggressive cancers with poor prognosis.
Benefits
- Highly potent MELK inhibitors with subnanomolar inhibition constants
- Targeted inhibition of MELK in cancer cell lines
- Potential therapeutic agents for triple-negative breast cancer and glioblastoma multiforme
- Reduction in cell viability and proliferation in cancer cells expressing high levels of MELK
- Improved selectivity and binding affinity through structural modifications
- Development of novel chemical probes for understanding MELK’s role in cancer
Commercial applications
- Cancer therapeutics
- Drug development
- Kinase inhibition
- Precision medicine
- Targeted therapy
Patent
Issued patent US 10,981,896