Table 1.

Overview of Compounds With Activity Against MCL-1 Currently Undergoing Clinical Evaluation

				Clinical Trials*
Compound	Category/Binding Site	In Vitro Potency	In Vitro or In Vivo Properties	Identifier	Study Phase	Treatment Regimen/Route of Administration	Tumor Type
Currently undergoing clinical evaluation
AZD5991 [17, 86]	MCL-1 inhibition via BAK-dependent mechanism/ ligand-binding pocket	KI: 200 pM IC50: 0.72 nM	100% tumor regression in mouse models after single dose; synergistic in vivo efficacy with SOC regimens	NCT03218683	1	Dose finding, administration every 21 days for 9 cycles/IV	Relapsed or refractory hematologic malignancies
S63845 [19]	Inhibition of MCL-1/BAK interaction/BH3-binding groove	KI: <1.2 nM Kd: 0.19 nM	25 mg/kg well tolerated and highly effective against mouse tumors	–	–	–	–
S64315 (MIK665) [83]	–	–	–	NCT02992483	1	Part 1: dose finding/IV Part 2: expansion study of RDE/IV	Relapsed or refractory lymphoma or MM
				NCT02979366	1	Starting dose: 50 mg once weekly/IV	AML, MDS
				NCT03672695	1	Recommended phase 2 dose finding study in combination with venetoclax/S64315, IV; venetoclax, oral	AML
AMG 176 [62, 84]	Selective MCL-1 inhibition/BH3-binding groove	KI: <1 nM	Rapid and robust induction of apoptosis in tumor xenografts after a single dose	NCT02675452	1	Part 1: dose finding/IV Part 2: combination regimens/IV	Relapsed or refractory MM or AML
				NCT03797261	1	Dose finding: various combinations of AMG 176 and venetoclax/AMG176, IV; venetoclax, oral	Relapsed or refractory hematologic malignancies
AMG 397 [85]	Selective MCL-1 inhibition/–	–	–	NCT03465540	1	Dose finding/oral	Relapsed or refractory MM, AML, NHL

AML=acute myeloid leukemia; BH3=BCL-2 homology 3; IC₅₀=concentration inhibitory to 50% of cells; IV=intravenous; MCL-1=myeloid cell leukemia sequence 1; MDS=myelodysplastic syndrome; MM=multiple myeloma; NHL=non-Hodgkin lymphoma; RDE=recommended dose for expansion; SOC=standard of care.

^*Clinical trial data available from www.ClinicalTrials.gov.