Table 1.

Summary of best c-MYC G4 ligands’ characteristics.

		Binding to c-MYC G4			Anticancer Activity
Group	N°	Strength (Kd, Ka, ΔTm)	Preference for c-MYC G4 (Yes/No)	In Vitro	In Vivo	Ref.
Macrocycles	1		No	Reduces telomerase activity. Decreases c-MYC and hTERT expression. Inhibits cancer cell growth.	Inhibits tumor growth in two xenograft tumor models.	[55,56]
	3	ΔTm = 17.2 °C	No	Decreases c-MYC expression. Decreases Pif1 helicase activity. Cytotoxicity activity (IC50 < 0.01 µM) in MCF-7 cells.		[58,59]
Ligands with four or more fused aromatic rings	4		Yes	Decreases c-MYC expression. Antiproliferative activity in cancer cells (IC50 = 0.24–4.8 µM).		[63]
	5	ΔTm = 26.6 °C	__	Decreases c-MYC expression. Cytotoxicity activity (IC50 of 4.7 µM) in Burkitt’s lymphoma (RAJI) cell line.	Inhibits tumor growth in a Burkitt’s lymphoma xenograft model.	[61]
	6 7	ΔTm = 7 °C ΔTm = 17 °C	No	Cytotoxicity activity (IC50 2.3–3.1 µM) in RAJI cell lines.		[64]
	8 9 10	ΔTm = 22.0 °C ΔTm = 16.6 °C ΔTm = 13.7 °C	Yes	Decrease c-MYC expression. Cytotoxicity activity (IC50 = 0.02–5.53 µM) for different cancer cell lines.	Compound 10 significantly decreases tumor growth in a lung cancer xenograft model.	[65]
	12	ΔTm = 21 °C	__	Decreases c-MYC expression.		[69]
	13	ΔTm > 15 °C	__	Specific toxicity against BRCA1/2-deficient cells. Inhibits RNA-polymerase I activity and the formation of nucleolin/G4 complexes. Decreases c-MYC expression and induces apoptosis.	Reached Phase II clinical trial.	[73,76]
	14	ΔTm > 15 °C	No	Specific toxicity against BRCA1/2-deficient cells. Inhibits RNA polymerase I and Topoisomerase II. Induces G4-mediated DNA damage.	Phase I clinical trial.	[81,131]
	15	ΔTm = 4.4 °C	__	Decreases c-MYC expression. Cytotoxicity activity (IC50 = 1.1 μM) in CNE-1 cells.	Inhibits tumor growth of CNE-1 cells in zebrafish xenograft model.	[82]
	16	-	No	Decreases c-MYC expression in mRNA. Cytotoxicity activity in different cell lines. ∙	Phase I clinical trial for acute myelogenous leukemia.	[83,85,86]
	17 18	ΔTm ~ 10 °C	Yes	Inhibits lymphoma cell growth.		[87]
	19	ΔTm = 16.4 °C	No	Decreases the expression of c-MYC and BCL-2. Causes telomere uncapping. Cytotoxicity activity in different cell lines.	Inhibits tumor growth in a metastatic lymph node cell in mice xenograft model.	[88,89]
	20	ΔTm > 6 °C	No	Decreases the expression of c-MYC and HIF1α.	Inhibits tumor growth in a colon cancer mouse model.	[91]
	21	ΔTm = 29 °C	Yes	Decreases c-MYC expression. Cytotoxicity activity in NCI cells (IC50 = 4 µM).		[92]
Ligands with three fused aromatic rings	22		Yes	Decreases c-MYC level by 25–40% in Ramos cells.	-	[95]
	24	ΔTm = 12.8 °C	No	Decreases c-MYC and BCL2 expression. Cytotoxicity activity in Jurkat human T lymphoblastoid cells (IC50 = 17.0 µM).		[96]
	26	ΔTm = 20 °C	Yes	Decreases c-MYC expression. Cytotoxicity activity in different cancer cell lines (IC50 = 2.1–4.2 µM).	Inhibits tumor growth in cervical squamous cancer in nude mice xenograft model.	[97]
	27 28	ΔTm = 4 °C ΔTm = 1.9 °C	Yes	Decreases c-MYC expression. Cytotoxicity activity in different cancer cell lines.		[98,99]
	29	ΔTm= 15.8 °C	Yes	Cytotoxicity activity in HeLa (IC50 = 3.4 µM) and in HCT116 (IC50 = 3.2µM) cells.		[100]
	31	Kd = 0.17 µM	__	Decreases c-MYC expression. Cytotoxicity activity in HCT116 cells (IC50 = 2.1 µM).		[102]
	34	ΔTm = 23.4 °C	__	Decreases c-MYC expression. Cytotoxicity activity in HeLa (IC50 = 2.5 µM) and in A549 (IC50 = 6.4 µM) cells.		[103]
	37	Kd = 36 nM	Yes	Decreases c-MYC expression.		[104]
	38	ΔTm = 15.0 °C	__	Decreases c-MYC expression. Downregulates RNA polymerase I transcription. Antiproliferative activity in different cancer cell lines.		[107]
Ligands with two fused aromatic rings	39	ΔTm = 23.7 °C	__	Decreases c-MYC expression.	Inhibits tumor growth in liver cancer in nude mouse xenograft model.	[108]
	40	ΔTm = 9 °C	__	Decreases c-MYC expression. Showed good binding affinity to NM23-H2 protein (KD = 5.29 µM).		[109]
	41 42	ΔTm = 12.1 °C ΔTm = 12.9 °C	__	Decrease c-MYC expression. Interfere with the binding of c-MYC G4 with NM23-H2.	Inhibit proliferation of SiHa cells in a dose-dependent manner.	[110]
	43	Binding affinity to NM23-H2 protein (KD = 3.1 μM)	No	Decreases c-MYC expression by disrupting the interaction between NM23-H2 and c-MYC G4. Induces cell cycle arrest and apoptosis. Cytotoxicity activity in different cancer cells.	Inhibits tumor growth in a cervical squamous cancer xenograft mouse model.	[111]
	44	KD = 1.3 μM	Yes	Decreases c-MYC expression. Cytotoxicity activity in different cancer cells (IC50 = 0.7–0.9 µM).	Inhibits tumor growth in a breast cancer xenograft mouse model.	[114]
	45	ΔTm = 15 °C	Yes	Decreases c-MYC expression. Cytotoxicity activity in melanoma cells (IC50 = 2.2 µM). Induces apoptosis.	Inhibits tumor growth in a melanoma mouse model.	[115]
	46	Ka = 9.9 × 105 M−1	Yes	Decreases c-MYC expression.		[116]
	47	Ka = 106.1 M−1	No	Acts as dual G4 binder/PARP inhibitor. Cytotoxicity activity in HCC1937 cells (IC50 = 19.4 µM).	Inhibits tumor growth in a breast cancer xenograft mouse model.	[117,118]
	48		Yes	Decreases c-MYC expression. Antiproliferative activity in different myeloma cell lines (IC50 = 5.8 µM).		[119,120]
	49	ΔTm = 7.5 °C	Yes	Decreases c-MYC expression. Cytotoxicity activity in myeloma cells (IC50 =3.4 µM).		[121]
Flexible ligands	52	ΔTm = 22 °C	Yes	Decreases c-MYC expression. Cytotoxicity activity in HeLa cells (IC50 = 3.8 µM) and in A549 cells (IC50 =3.2 µM).		[122]
	53 54	ΔTm = 15.0 °C ΔTm = 6.0 °C	No	Decrease c-MYC expression. Cytotoxic activity in MCF-7 cells (IC50 = 3.80 and 7.1 µM, respectively).	-	[124,125]
Metal complexes	56 57 58 59	ΔTm = 10.2 °C ΔTm = 15.6 °C ΔTm = 2.0 °C ΔTm = 7.3 °C	No	Decrease c-MYC expression.		[128]
	60 61		__	Decrease c-MYC expression. Cytotoxic activity in Hep-G2 cells (IC50 = 10.1 and 5.1 µM, respectively).		[129]