Table 1.

Investigational agents targeting protein homeostasis in MM. This table outlines promising agents targeting protein homeostasis in advanced preclinical or early clinical development in MM, in different phases of a clinical trial

Drug name	Target molecule/mechanism of action	Status	Study design	Clinical trial identifier/PMID
Proteasome inhibitors
Marizomib (NPI-0052)	• Targets all three proteasomal subunits • PolyUb protein accumulation • Caspase 8- and 9-mediated apoptosis	Phase I completed	Marizomib + POM + DEX in RRMM	NCT02103335
		Phase II completed	Marizomib alone in RRMM	NCT00461045
		Phase I completed	Marizomib + Vorinostat in RRMM	NCT00667082
		Phase I completed	Marizomib + DEX	NCT02103335
Oprozomib (ONX 0912, PR-047)	• Inhibits PSMB5 (proteasome), LMP7 (immunoproteasome) • PolyUb protein accumulation and terminal UPR induction • Caspase 8- and 9-mediated apoptosis • p53 and p21 upregulation • miR33b upregulation • PIM1 downregulation • Anti-angiogenesis	Phase Ib/II completed	Oprozomib alone	NCT01416428
		Phase I/II completed	Oprozomib + DEX + LEN/CPM in NDMM	NCT01881789
		Phase Ib/II terminated	Oprozomib + DEX in RRMM	NCT01832727
		Phase I/II completed	Oprozomib + POM + DEX in RRMM	NCT01999335
		Phase I active	Oprozomib IR or GR formulations + DEX + POM in RRMM	NCT02939183
		Phase Ib/II completed	Oprozomib + Melphalan + Prednisone in NDMM (transplant-ineligible)	NCT02072863
DUBs and ubiquitin receptors inhibitors
VLX1570	• Inhibits proteasome USP14 activity	Phase I/II terminated	VLX1570 + DEX in RRMM	NCT02372240
P5091	• Inhibits proteasome USP7 activity	Preclinical	N/A	PMID: 22975377[58]
B-AP15	• Blocks USP14 and UCHL5 • Growth arrest via downregulation of CDC25C, CDC2, and cyclin B1 • Induction of caspase-dependent apoptosis • Activation of UPR	Preclinical	N/A	PMID: 24319254[145]
RA190	• Inhibits RPN13 and UCHL37	Preclinical	N/A	PMID: 27118409[60]
XL177A	• Inhibits USP7	Preclinical	N/A	PMID: 32210275[67]
HDAC inhibitors
Ricolinostat (ACY-1215)	• Inhibits HDAC6 • Caspase 8 and 9 mediated apoptosis • PolyUb protein accumulation and terminal UPR induction • Aggresome disruption	Phase Ib/II active	Ricolinostat + POM + DEX in RRMM	NCT02400242
		Phase I/II active	Ricolinostat + LEN + DEX in RRMM	NCT01583283
		Phase I/II completed	Ricolinostat + BTZ + DEX in RRMM	NCT01323751
Citarinostat (ACY-241)	• Inhibits HDAC6 • Downregulation of MYC and IRF4 • Aggresome disruption	Phase I	Citarinostat + POM + DEX in RRMM	NCT02400242
Autophagy inhibitors
Chloroquine	• Inhibits autophagy alkalinizing the lysosomal pH and inhibiting autophagosome and lysosome fusion	Phase I	Chloroquine + BTZ + CPM in RRMM	NCT01438177
3-MA	• Inhibits autophagy at the level of PI3K Class III	Preclinical	N/A	PMID: 19648108[146]
Bafilomycin A1	• Inhibits autophagosome and lysosome fusion	Preclinical	N/A	PMID: 21174067[93]
Unfolded protein response modulators
Nelfinavir	• Triggers pro-apoptotic PERK pathway • Inhibition of AKT phosphorylation	Phase I/II active	Nelfinavir + LEN + DEX in progressive MM	NCT01555281
		Phase I active	Nelfinavir + BTZ + Metformin in RRMM	NCT03829020
		Phase II completed	Nelfinavir + BTX + DEX in refractory MM	NCT02188537
Sunitinib	• Inhibition of IRE1 activity	Phase II	Sunitinib malate in relapsed MM	NCT00514137
Lovastatin, zolendronic acid, digeranyl bisphosphonate	• Inhibition of isoprenoid biosynthetic pathway and Rab geranyl • Ig light chain accumulation in the ER - activation of UPR	Preclinical	N/A	PMID: 20828814[147]
4μ8C	• Inhibition of XBP1 mRNA splicing	Preclinical	N/A	PMID: 22315414[148]
MAL3-101	• Induction of XBP1 mRNA splicing following inhibition of HSP70	Preclinical	N/A	PMID: 22750096[149]
MKC-3946	• Inhibition of XBP1 mRNA splicing	Preclinical	N/A	PMID: 14559994[40]
STF-083010	• Inhibition of XBP1 mRNA splicing	Preclinical	N/A	PMID: 21081713[106]
GSK2656157	• Inhibition of PERK and eIF2α phosphorylation, ATF4 translation, and CHOP mRNA expression	Preclinical	N/A	PMID: 23333938[150]
CB-5083	• p97 inhibition - polyUb protein accumulation - UPR induction and apoptosis	Phase I terminated	CB-5083 + DEX	NCT02243917
PAT-SM6	• Inhibition of GRP78-UPR induction • Complement-dependent cytotoxicity	Phase I completed	PAT-SM6 single agent in RRMM	NCT01727778
Heat Shock Protein (HSP) Inhibitors
KW-2478	• HSP90 inhibitor • Apoptosis	Phase II completed	KW-2478 + BTZ in RRMM	NCT01063907
NVP-AUY922	• HSP90 inhibitor • Apoptosis • Downregulation of survival pathways	Phase I/II completed	NVP-AUY922 +/- BTZ +/- DEX in RRMM	NCT00708292
IPI-504	• HSP90 inhibitor • Inhibition of UPR	Phase I completed	IPI-504 in RRMM	NCT00113204
Tanespimycin (17-AAG, KOS-953)	• HSP90 inhibitor • Inhibition of downstream signaling pathways • Induction of UPR	Phase II/III completed	Tanespimycin + BTZ in RRMM	NCT00546780
SNX-5422	• HSP90 inhibitor • Apoptosis	Phase I completed	SNX-5422 in RRMM	NCT00595686
NVP-HSP990	• HSP90 inhibitor • Apoptosis • Cell cycle arrest	Preclinical	N/A	PMID: 22309072[133]
NVP-BEP800	• HSP90 inhibitor • Apoptosis • Inhibition of STAT3, ERK, AKT pathways	Preclinical	N/A	PMID: 19686236[151]
SNX-2112	• HSP90 inhibitor • Cell cycle arrest and cytotoxicity • Inhibition of ERK, AKT pathways • Inhibition of angiogenesis and osteoclastogenesis	Preclinical	N/A	PMID: 18948577[152]
MAL3-101	• Inhibition of HSP70 • Induction of XBP1 mRNA splicing • Apoptosis and cell cycle arrest	Preclinical	N/A	PMID: 22750096[149]
PU-H71	• Inhibition of HSP90 • Apoptosis and cell cycle arrest, UPR and apoptosis	Preclinical	N/A	PMID: 20977755[134]
TAS-116	• HSP90 inhibitor • Induction of apoptosis • Disruption of ERK, AKT pathways	Preclinical	N/A	PMID: 25306900[153]
Selective degradors
Phthalimide conjugated degraders	• Bind to CRBN E3 complex on one hand and to specific protein targets on the other to elicit proteasome-mediated degradation	Preclinical	N/A	PMID: 25999370[154]