Table 2.

Inhibitors targeting proteins involved in centrosome amplification (CA).

Inhibitors Targeting	Enzymes	Pathways	Protein Target	Inhibitor	Mechanism of Action of Inhibitors	Clinical Trial
Centrosome amplification (CA)	ATM/ATR kinases	DNA damage	ATM/ATR kinases	Caffeine	Induces G1/S arrest and abrogates the G1/S and G2/M checkpoint delay periods [84].	Phase I–IV studies in a wide range of solid tumours (lymphoma, small cell lung cancer, melanoma, kidney, pancreatic, ovarian and leukaemia). https://clinicaltrials.gov/ct2/results?cond=Cancer&term=caffeine&cntry=&state=&city=&dist=
	Chk1		Chk1	UCN-01	Binds the ATP-binding pocket of Chk1, resulting in accumulation of cells in G1 phase and induction of apoptosis [92].	Phase II clinical trials in lymphoma, small-cell lung cancer, melanoma, kidney, pancreatic, ovarian and leukaemia patients. https://clinicaltrials.gov/ct2/results?term=UCN-01&age_v=&gndr=&type=&rslt=&phase=1&Search=Apply
				MK-8776 (SCH 900776)	Radiosensitizes tumor cells by causing abrogation of the G2 block and DSB repair [93].	Phase II clinical trial completed in patients with relapsed acute myeloid leukaemia: NCT01870596.
	poly (ADP-ribose) polymerase (PARP)		PARP-1	3-Aminobenzamide (3-AB)	1st generation PARP inhibitor: shows structural similarity with nicotinimide and binds PARP preventing it from depleting NAD+. PARP-1 inhibition causes the uncoupling of DNA and centrosome duplication cycles leading to CA [87].	Pre-clinical development [89].
				Rucaparib (AG14361)	Hydrogen bonds with the Gly863, Ser904, and Glu988 residues of the PARP-1 protein [91].	Phase I/II/III trials in a range of human malignancies alone and in combination with other agents. https://clinicaltrials.gov/ct2/results?cond=Cancer&term=rucaparib&cntry=&state=&city=&dist=
				NU1025	Hydrogen bonds with the Gly863, Ser904, and Glu988 residues of the PARP-1 protein [91].	Pre-clinical development [88].
	Phosphoinositide 3-kinase (PI3K)	PI3K/Akt	PI3K/p110α	LY294002	Reversibly inhibits PI3K by competing with ATP for the active site of catalytic subunit p110 [94].	Phase I clinical trial in patients with relapsed or refractory neuroblastoma: NCT02337309.
				GDC-0941 Pictrelisib	Selectively binds to PI3K isoforms in an ATP-competitive manner and inhibits the production of the secondary messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3) [95].	Phase II clinical study in completed in breast cancer and non-small cell lung cancer. https://clinicaltrials.gov/ct2/results?term=GDC-0941&cond=cancer+and+neoplasia&age_v=&gndr=&type=&rslt=&phase=1&Search=Apply
				Wortmannin	Binds to the ATP-binding site of p110 by forming a covalent bond between C20 of the wortmannin furan ring and K802 of p110a [94].	Pre-clinical development.
				A66	Blocks insulin signalling to Akt/PKB by inhibiting p110α and reducing cell growth [96].	Pre-clinical development [97].
	Akt		Akt	MK-2206	Non-ATP competitive inhibitor of the PI3K/Akt signalling pathway causing decreased cell proliferation and induction of apoptosis [96].	Clinical trials in advanced breast cancer, metastatic neuroendocrine tumors (NET), advanced colorectal carcinoma, ovarian cancer, endometrial cancer and non-small cell lung cancer. https://clinicaltrials.gov/ct2/results?cond=cancer&term=MK-2206&cntry=&state=&city=&dist=&Search=Search
	Mtor p70S6 kinase			Akti X	Inhibits phosphorylation of mTOR, p70S6 kinase and S6 ribosomal protein resulting in apoptosis [96].	Phase I clinical trial in cancer patients with metastatic melanoma: NCT02489266.
	PI3K /Mtor			PF-04691502	ATP-competitive PI3K/mTOR dual inhibitor, which potently inhibits recombinant class I PI3K and mTOR [98].	Phase II clinical trial in patients with breast cancer (NCT01658176, NCT01430585) and endometrial cancer (NCT01420081).
	ROCK1 and ROCK2	RhoA/ROCK	ROCK	Y27632	Y-27632 inhibits both ROCK1 and ROCK2 by competing with ATP for binding to the catalytic site [96,99].	Pre-clinical trials [99].
				H1152	ATP-competitive inhibitor of G-protein Rho-associated [96,99].	Pre-clinical trials [99].
	Plk4	Centriole duplication	Plk4	CFI-400945	ATP competitive inhibitor, inhibits autophosphorylation of Plk4 at serine 305 [30].	Phase I clinical trial in patients with advanced cancer (NCT01954316) and phase I study in patients with relapsed or refractory acute myeloid leukaemia or myelodysplastic syndrome (NCT03187288).