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Table 2 Targets and efficacy of PROTACs in hematologic malignancies

From: Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies

  In vitro efficacy In vivo efficacy  
Target E3 ligase Compound Disease Efficacy (EC50 or other ) Degradation (DC50/Dmax or other) Model and efficacy Degradation Ref.
ALK CRBN
TL13-112
ALCL Karpas299 (<50 nM); SU-DHL-1 (<50 nM) Karpas299 (DC50: 40 nM) NA NA [41]
Bcl-6 CRBN
PROTAC 15
DLBCL PROTAC 15 showed weak antiproliferative activity in DLBCL cell lines (>5μM) 1 μM of 15 caused 82% degradation of Bcl-6 in OCI-Ly1 NA NA [42]
Bcl-xL VHL
DT2216
T-ALL MOLT-4 (52 nM) MOLT-4 (DC50: 63 nM; Dmax: 90.8%) MOLT-4 xenograft: Once weekly dosing of DT2216 completely inhibited MOLT-4 xenograft
CUL76 T-ALL PDX: Combination of DT2216 with chemotherapy drug substantially increased survival
MOLT-4 xenograft: Single dose of DT2216 at 15 mg/kg caused sustained reduction in Bcl-xL in MOLT-4 xenograft [4]
BCR-ABL VHL
SIAIS178
CML K562 (24 nM) K562 (DC50: 8.5 nM) K562-Luc xenograft: SIAIS178 at 5 and 15 mg/kg/day, i.p. for 12 days dose-dependently inhibited tumor growth K562 xenograft: SIAIS178 at 5 and 15 mg/kg/day, i.p. for 4 days dose-dependently depleted BCR-ABL levels in tumors 6 h after last dose [6]
BRD4 CRBN
dBET6
T-ALL In a set of 20 T-ALL lines, such as SUPT11(<10 nM) MOLT4 (DC50< 10 nM) SUPT11 xenograft: dBET6 (7.5 mg/kg, twice daily) significantly reduced leukemic burden
MOLT-4 xenograft: dBET6 (7.5 mg/kg BID) exhibited a significant survival benefit in mice
SUPT11 xenograft:
dBET6 led to degradation of BRD4 in leukemic bone marrow 3 h after treatment
[43]
  VHL
ARV-771
MCL Mino (<20 nM), Z238 (~200 nM) Primary MCL cells (NA) Mino (NA); primary MCL cells (NA) Z138 xenograft: ARV-771 (30 mg/kg) was significantly more effective in improving the median and overall survival Z138 xenograft:
ARV-771 (30 mg/kg, daily for 5 days) resulted in the depletion of BRD4 from the spleen and bone marrow
[8]
BTK CRBN
DD-03-171
BCL TMD8-BTK WT (29.2 nM); TMD8-BTK C481S (128 nM); Mino (12 nM) Effectively degraded BTK at concentrations as low as 100 nM within 4 hours of treatment in Ramos B cells DLBCL and MCL PDX models: DD-03-171 at 50 mg/kg/day, i.p. for 14 days significantly inhibited the tumor burden and enhanced the survival of DFBL-96069-engrafted mice DLBCL and MCL PDX models: DD-03-171 at 50 mg/kg/day, i.p. for 3 days depleted BTK levels in the spleens of DFBL-96069-engrafted mice [44]
CDK6 CRBN
YX-2-017
Ph+ ALL BV173 (NA); SUP-B15 (NA) BV173 (4 nM); MUTZ-5 (NA); MHH-CALL-4 (NA); SEM (NA); Jurkat (NA) Ph+ALL xenografts: YX-2-107 suppressed S-phase cell percentage and decreased phosphor-RB and FOXM1 expression in bone marrow cells
Ph+ALL PDX: YX-2-107 suppressed peripheral blood leukemia burden
Ph+ALL xenografts: NSG mice were given YX-2-107 at 150 mg/kg per day for 3 consecutive days. YX-2-107 reduced CDK6 level in bone marrow cells [9]
FLT-3 VHL
FLT-3 PROTAC
AML MV4-11 (0.6 nM); MOLM-14 (NA); OCIAML-3 (>2.8 μM) MV4-11 (NA) NA MV4-11 xenograft : FLT-3 PROTAC at 30 mg/kg daily for 3 d decreased FLT-3 by 60% in tumor [10]
HDAC6 CRBN
12d
MM MM.1S (EC50=74.9 nM, Emax=63.1%) MM.1S (DC50: 1.6 nM) NA NA [11]
Mcl-1 CRBN
dMCL1-2
MM NA OPM2 (NA)
MM.1S (NA)
NA NA [45]
MDM2 CRBN
MD-224
ALL; AML RS4-11 (1.5 nM);
MOLM-13 (7.3 nM);
MOLM-14 (10.5 nM);
SIG-M5 (19.8 nM);
ML-2 (4.4 nM)
OCL-AML-5 (33.1 nM)
Effectively induced marked depletion of MDM2 at 1 nM in RS4-11 cells RS4-11 xenograft: MD-224 at 25 mg/kg, daily, 5 days a week for 2 weeks, or at 50 mg/kg, every other day for 3 weeks achieved complete tumor regression RS4-11 xenograft: Single intravenous dose of MD-224 effectively depleted MDM2 protein at 3 h, with the effect persisting for >24 h [46]
PRC2 VHL
UNC6852
DLBCL DB (3.4 μM)
Pfeiffer (0.41 μM)
DB (DC50/Dmax):
EED 0.61 μM/96%; EZH2 0.67 μM/94%; SUZ12 0.59 μM/82%)
NA NA [47]
SMARCA2/4, PBRM1PBRM1 VHL
ACBI1
AML MV-4-11 (29 nM) MV-4-11 cell (6 nM (SMARCA2), 11 nM (SMARCA4), 32 nM (PBRM1)), Dmax = 100% for SMARCA2/4 and PBRM1 NA NA [48]
STAT3 CRBN
SD-36
AML;
ALCL
AML: MOLM-16 (0.035 μM)
ALCL: SU-DHL-1 (0.25 μM); SUP-M2 (0.13 μM); KI-JK (0.18 μM); Karpas-299 (0.98 μM); DEL (1.48 μM);
MOLM-16 (Dmax: 90%) MOLM-16 xenograft: SD-36 at 100 mg/kg weekly or 50 mg/kg twice weekly for 4 weeks induced complete tumor regression; SUP-M2 xenograft: SD-36 at 50 mg/kg 3 times per week completely inhibited tumor growth. SD-36 at 100 mg/kg 3 times per week achieved complete tumor regression MOLM-16 xenograft: Single dose of 25 mg/kg SD-36 depleted STAT3 protein by >80% in MOLM-16 engrafted tumors; SU-DHL-1 xenograft: Single dose of SD-36 near-completely depleted STAT3 protein in SU-DHL-1 engrafted tumor [3]
  1. ALCL anaplastic large-cell lymphoma, ALL acute lymphoblastic leukemia, AML acute myeloid leukemia, BCL B cell lymphoma, CML chronic myelogenous leukemia, DLBCL diffused large B cell lymphoma, MCL mantle cell lymphoma, MM multiple myeloma, Ph+ ALL Philadelphia chromosome-positive acute lymphoblastic leukemia, T-ALL T cell acute lymphoblastic leukemia