Biology subjects

Kalashova, J.

Publications and source records attributed to Kalashova, J..

3 recordsLinked to original sources

bioRxiv2023

MYC amplifies mitotic perturbations elicited by LXY18 to enable synthetic lethality

The MYC oncoprotein represents an intriguing target for cancer treatment, but its therapeutic potential has been hindered by the absence of specific pharmacological inhibitors. In this study, we demonstrate that the phenoxy quinoline compound LXY18 selectively targets and eliminates cells overexpressing MYC, leaving non-transformed cells unharmed. This synthetic lethality arises from an acute induction of multipolarity, resulting in a persistent arrest in early mitosis followed by cell death in mitosis or after mitotic slippage. Distinctively, LXY18s action contrasts with other antimitotic compounds, as they either fail to induce mitotic arrest or elicit mitotic arrest irrespective of MYC abundance. Furthermore, the MYC abundance in a panel of 98 tumor cell lines correlates with their sensitivity to LXY18. Collectively, our findings uncover LXY18 as an MYC- enabled mitotic blocker and open a new avenue to selectively target MYC-overexpressing tumor cells without affecting normal cells.

cancer biology↗

bioRxiv2023

Characterization of mitotic phenotypes associated with a MYC synthetic lethal compound

Therapeutic targeting of MYC directly has proven difficult, but several means to target MYC indirectly using a synthetic lethal drug approach have been proposed. Synthetic lethal approaches for MYC have sought to take advantage of vulnerabilities MYC imposes related to either metabolic reprogramming, apoptotic signaling or the cycling of cancer cells. Here, we describe in detail the cell division phenotypes induced by a MYC synthetic lethal compound, dimethylfasudil (diMF). DiMF is a known ROCK inhibitor, but structurally related ROCK inhibitors are not synthetic lethal with MYC, so the activity of diMF is not related to blockade of this family of kinases. Instead, this compound induced multiple cell cycle-related liabilities. These included the early mitotic arrest of cycling cells followed by mitotic catastrophe-induced death and the induction of polyploidy in cells that do manage to pass through mitosis. As early as prometaphase, we noted diminished staining for BUB1 kinase, which binds to kinetochores and regulates the mitotic spindle checkpoint and chromosome congression. Kinetochore proteins, such as CENP-F, failed to localize at the metaphase plate, confirming a deficit in centromere assembly. This, presumably, contributed to the development of segregation anomalies in diMF-treated cells. In anaphase cells, the protein regulator of cytokinesis 1 (PRC1), failed to be recruited to the midzone, leading to a cascade of defects that included failed recruitment of the chromosomal passenger protein complex, the centralspindlin complex and polo-like-kinase 1 (PLK1). These observations correlate well with the cell death phenotypes induced by diMF, which may serve as a prototype MYC synthetic lethal compound to explore synthetic lethal therapy or as a scaffold upon which to build superior compounds. The phenotypes described here serve as examples of MYC synthetic lethal drug effects that can be used to explore and maximize drug discovery programs.

cancer biology↗

bioRxiv2023

An orally bioavailable 4-phenoxy-quinoline compound as a potent AURKB relocation blocker for cancer treatment

We investigated a novel 4-phenoxy-quinoline-based scaffold that mislocalizes the essential mitotic kinase, AURKB. Here, we evaluated the impact of halogen substitutions (F, Cl, Br, I) on this scaffold with respect to various drug parameters. Br-substituted LXY18 was found to be a potent and orally bioavailable disruptor of cell division, at sub-nanomolar concentrations. LXY18 prevents cytokinesis by blocking AURKB relocalization in mitosis and exhibits broad-spectrum antimitotic activity in vitro. With a favorable PK profile, it shows widespread tissue distribution including the blood-brain barrier penetrance and effective accumulation in tumor tissues. More importantly, it markedly suppresses tumor growth. The novel mode of action of LXY18 may eliminate some drawbacks of direct catalytic inhibition of AURKs. Successful development of LXY18 as a clinical candidate for cancer treatment could enable a new, less toxic means of antimitotic attack that avoids drug resistance mechanisms.

cancer biology↗