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] |
