Investigating monopolar spindle 1 as a target for drug therapy

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Introduction

Cell cycle is a sophisticated process which enables cell to faithfully replicate it’s DNA and divide subsequently under surveillance mechanism. These mechanisms are often termed as check points. One such check point resides in the mitosis phase of cell cycle known as Spindle Assembly Checkpoint (SAC)1,2. SAC enables cell to halt progression in anaphase until kinetochores are properly attached to chromosomes and posses tension in them. Among the myriad of components that functions at SAC is monopolar spindle 1 (MPS1)3. MPS1, initially identified in budding yeast3, is found in number of, but not ubiquitous to, eukaryotes. MPS1 is a dual-specific protein kinase4 that is implicated to regulate a number of steps in mitosis and cell division. Initial studies revealed that yeast mutant for MPS1 lead to the formation of aberrant monopolar spindle and also failed to promote mitotic arrest. Similar to other cell cycle components, MPS1 has been found to be misregulated in variety of human tumors. Elevated expression of MPS1 has been found in papillary carcinoma, bronchogenic carcinoma, and breast5, thyroid6, esophagus7 and lung cancers8. Conversely, MPS1 expression has been found to be reduced in the cells with low proliferative index. Taken together, these results indicate a direct correlation between increased levels of MPS1 with proliferation, as seen in aggressive tumors. In line with this, MPS1 is found to be among one of the 25 signature genes that which are over expressed in CIN and aneuploid9,10 tumors resulting from chromosomal instability11. These findings indicate MPS1 to be an effective drug target for cancer therapeutics. In the same vein, crucial role of MPS1 kinases in mitotsis and it’s over expression in number of tumors has spurred significant interest in development of Mps1 inhibitors which may act as a potent anticancer drug.

MPS1 as a drug target can be a putative therapeutic approach.

Selective inhibition of MPS1 has recently emerged a promising approach towards cancer therapeutics. In contract to the canonical anti-mitotic cancer therapies, pharmacological inhibition of MPS1 can result in abrogation of SAC which will consequently induce vast aneuploidy. This large scale aneuploidization usually results in cell death. Hence, purpose of such treatment is not to restrict proliferation but to disrupt SAC which consequently results in catastrophic mitosis and, hence, increased aneuploidy which ultimately leads to cell death. Adding to it, MPS1 is known to be mis-regulated in number of tumors which indicates the fact that the SAC is essential for the viability and propagation of aneuploid tumor cells. These findings have spurred the interest of developing potent drugs against targets like MPS1 in order to combat cancer in a

Inhibitors of MPS1

Table 1 List of small molecule inhibitors developed against MPS1

Inhibitor (molecule)

IC50(nM)

Reference

SP600125

692

12-14

AZ3146

35

15

Mps1-IN-1

370

16

Mps1-IN-2

145

16

Mps1-IN-3

50

17

NMS-P715

8

18

MPI-0479605

3.5

19,20

Reversine

3/6

21

Cpd4

38,000

13

Cincreasin

50

22

1H‑Pyrrolo[3,2‑c]pyridine

23

To date, several inhibitors of MPS1 have been identified. Among these inhibitors, cincresin has shown to be effective only in yeast 22. When tested on mammalian cells, cincresin failed to arrest SAC. Hence, cincesin developed as a drug in cancer therapeutics largely failed. On the other hand, SP600125 was identified the first mammalian MPS1 inhibitor14. Although SP600125 was originally identified as c-Jun amino-terminal kinase (JNK) inhibitor, it was shown that this chemical inhibitor inactivated SAC too. One of the reasons for this can be structural similarity of the ATP-binding domain of JNK and the MPS1 kinase domain. However, this drug has been shown, in-vitro, to inhibit an array of other kinases too24 and hence will not serve as a selective drug against MPS1. In addition to it, number of cancer cell lines have been shown to be develop resistance to SP600125 mediated inactivation of SAC14. This makes SP600125 relatively irrelevant drug to ever make it to clinical trials.

After the identification of SP600125, number of other Mps1 inhibitors were characterized which including AZ314615. In-vitro kinase assays demonstrated that AZ3146 has the potential to inhibit human Mps1with an IC50 of 35nM. Same study revealed that AZ3146 is also capable of efficiently inhibiting autophosphorylated Mps1 extracted from various human cells. Hence, AZ3146 came out as a potent inhibitor of Mps1. This compound also showed selectivity for Mps1 over 46 other kinases which also included Cdk1 and aurora kinase B.

Mps1-In-1 and Mps1-In-2 were also identified as inhibitors of MPS1. Co-crystal structures of these inhibitors with Mps1 kinase domain revealed that these inhibitors bind to the ATP binding pocket of Mps1 via hydrogen bond interaction with the hinge backbone (E603).Moreover, treating HCT116 cell lines with these inhibitors resulted in 33% reduced proliferative capacity and large scale aneuploidy. However, potency of the inhibitors was found to have moderate potency IC50 of 367 nM and 145 nM for Mps1-In-1 and Mps1-In-2 respectively. These chemical compounds were also find to inhibit other kinases of interest too which may elicit few off-side responses of this compound as a potential drug against MPS1. In addition to it, another compound, of the same class, was identified as the inhibitor of MPS1 named MPS1-IN-3. Although initially minimal toxicitywas observed for the MPS1-IN-3 in combination with vincritine, there is certain limitation involved with this drug which needs to be surpassed before clearance for any clinical studies. Firstly, MPS1-IN-3 has only been tested on limited number of glioblastoma celllines in combination with vincristine. Hence, it would be of sheer interest to gauge the subsequent effects of MPS1 inhibition in an array of primary cancer cell lines.

Another inhibitor known as Reversin was previously shown to target AURORA kinases in vitro and in vivo25,26. However, unlike SP600125 it’s role as a potent inhibitor for MPS1 is reported in both yeast22 and human cell lines21. However, as mentioned earlier that (reversine) is a nonselective inhibitor of MPS1 as it known to inhibit MPS1, Aurora A, and Aurora B. on the other hand, another potent small molecule inhibitor for Mps1 is MPI-0479605. Consistent with the treatment of other Mps1 inhibitors, MPI-0479605 inhibition also leads to impairment of SAC, mitotic catastrophe and eventually leading to massive cell death due to aneplody. However, few side-effects were observed in the mice treated for this molecule which indicated that MPI-0479605 was also affecting the normal cells20.

All the above mentioned inhibitors are mostly first generation non selective inhibitors. NMS-P715 was the first selective and orally bioavailable inhibitor developed for MPS117. It is one of the most potent and selective inhibitor reported for Mps1 to date. Cell treated with NMS-P715 exhibited all the hallmarks of SAC failure which includes misalignment of chromosomes, reduced mitosis, large-scale aneuploidization which consequently lead to cell death in a range of cancer cell lines. Moreover, this inhibitor is shown to have significant effect on cancer cell lines and mouse models which a minimal effect on normal cells. Authors for this work do comment on the therapeutic potential of this compound. However, no report for it’s further development is seen so far and this compound await its development toward clinical studies as a potent target for cancer therapeutics.

In addition to it, selective and bioavailable inhibitor of MPS1 was reported23. This potent small molecule inhibitor was based on 1H-pyrrolo[3,2-c]- pyridine scaffold. Final structure-based optimized compound was shown to display efficient and selective inhibition of MPS1 in-vitro and cellular assays. Moreover, X-ray crystallographic structure studies confirmed that this compound stabilizes the activation-loop in MPS1 which eventually occluded ATP-binding site and hence led to inhibition of MPS1. This compound is reported to show a promising pharmacokinetic profile in mice and in vivo inhibition of MPS1 subsequent to oral administration.

Conclusion

Although number of inhibitors has been reported to be developed against MPS1, most of them never made it to the clinical studies so far. One of the major reasons for this is that most of these inhibitors are non-selective which may confer side-effect in therapeutics. There have been number of limitations towards developing cancer drugs using such inhibitors. Not only this but there is a dire need of conducting more studies h to characterize basic properties of this compounds as a potential drug against MPS1, which includes half-life of the drug, it’s ability to cross the blood brain barrier and drug pump substrate specificity. Moreover, it is important to consider the effect of tumor heterogeneity in the response to the treatment using such inhibitors. Hence, before any clinical studies it would be important to study the effects of such inhibitors using different samples from the same tumor. Taken together, with the advent of orally bioavailable inhibitors there is a hope of developing new drugs which, unlike conventional anti-mitotic cancer drugs, with open window for new approaches in cancer therapeutics.

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