Table 3.
Known modulators of pseudokinase function
| Molecule or antibody name | Type | Mechanism of action | Refs |
|---|---|---|---|
| EPHA10 | |||
| BsAb | mAb | Bispecific antibody that targets EPHA10 and CD3; induces redirected T cell-mediated lysis of EPHA10-overexpressing cells | 257 |
| Db-1 and Db-2 | Diabody | Heterodimeric (Db-1) and homodimeric (Db-2) diabodies that target EPHA10 and CD3; induce redirected T cell-mediated lysis of EPHA10-overexpressing cells | 279 |
| HER3 | |||
| Elgemtumab (LJM716) | mAb | Binds to inactive conformation of ECD but does not prevent ligand binding; inhibits ligand-dependent and ligand-independent HER3 signalling | 280 |
| Duligotuzumab (MEHD-7945A) | mAb | Dual specificity antibody that recognizes the inactive conformations of the HER3 and EGFR ECDs; blocks ligand binding | 248, 249 |
| Seribantumab (MM-121) | mAb | Inhibits ligand-induced phosphorylation of HER3 | 242 |
| Patritumab (U3–1287 or AMG-888) | mAb | Promotes receptor internalization; inhibits ligand-induced HER3 signalling | 245, 246, 281 |
| U3–1402 | ADC | ADC consisting of patritumab conjugated to the topoisomerase I inhibitor DX-8951 | 282 |
| Lumretuzumab (RG7116) | mAb | Binds to inactive conformation of ECD and blocks ligand binding; inhibits ligand-induced HER3 signalling; exhibits enhanced ADCC due to glycoengineering of Fc moiety | 243 |
| FL518 | mAb | Four-in-one antibody made by combining duligotuzumab and bH1–44 that recognizes EGFR, HER2, HER3 and VEGF; inhibits ligand-dependent and ligand-independent signalling | 252 |
| AV-203 | mAb | Blocks ligand binding and prevents dimerization with HER2; inhibits ligand-dependent and ligand-independent HER3 signalling | 283 |
| GSK2849330 | mAb | Disrupts ligand-dependent HER3 signalling; engineered to exhibit enhanced ADCC and cell division cycle | 284 |
| KTN3379 | mAb | Prevents HER2–HER3 heterodimerization; inhibits both ligand-dependent and ligand-independent HER3 signalling | 285 |
| REGN1400 | mAb | Blocks ligand binding | 286 |
| MCLA-128 | mAb | Bispecific antibody targeting both HER2 and HER3 that exhibits enhanced ADCC | 287 |
| TX2–121-1 | Small molecule | Irreversible ATP-competitive inhibitor that forms covalent adduct with Cys721 in HER3; induces degradation of HER3 and interferes with heterodimerization with HER2 and MET | 232 |
| Bosutinib | Small molecule | ATP-competitive SRC and ABL inhibitor that promotes HER3 heterodimerization with HER2 and promotes proliferation of HER2+ breast cancer cells | 194 |
| CT8 | Small molecule | Binds Sec61 translocon and interferes with cotranslational insertion of HER3 into the ER, resulting in HER3 degradation | 235 |
| JAK2 JH2 | |||
| JNJ-7706621 | Small molecule | ATP-competitive pan-CDK and Aurora A and Aurora B inhibitor that binds to both JAK2 JH1 and JH2 | 203, 204 |
| AT-9283 | Small molecule | ATP-competitive Aurora A, Aurora B, JAK2 and JAK3 inhibitor that binds to both JAK2 JH1 and JH2 | 203 |
| KSR2 | |||
| APS-2–79 | Small molecule | ATP-competitive inhibitor that stabilizes an inactive conformation of the pseudokinase domain; prevents heterodimerization with RAF kinases and stabilizes inactive complex with MEK | 199 |
| ASC-24 | Small molecule | ATP-competitive inhibitor that blocks KSR kinase activity in vitro but does not prevent heterodimerization with RAF kinases | 172 |
| MLKL | |||
| Compound 1 | Small molecule | ATP-competitive VEGFR and RIPK1 inhibitor that stabilizes DFG-out conformation of MLKL pseudokinase domain; inhibits necroptosis | 99, 157 |
| Compound 4 | Small molecule | ATP-competitive small molecule that stabilizes DFG-in conformation of MLKL pseudokinase domain; more selective for MLKL than compound 1 but fails to inhibit necroptosis | 157 |
| PTK7 | |||
| PF-06647020 | ADC | ADC consisting of the anti-PTK7 mAb h6M24 conjugated to the auristatin microtubule inhibitor Aur0101 | 258 |
| RNase L | |||
| Sunitinib | Small molecule | ATP-competitive inhibitor of PKR, PDGFR and VEGFR; inhibits RNase L activity and dimerization | 206 |
| Flavonols | Small molecule | ATP-competitive activators of yeast IRE1 RNase activity; inhibit RNase L activation | 206 |
| ROR1 | |||
| 3B8, 1C11, 1D8, 4C10, 4A7 | mAb | mAbs raised against immunoglobulin (3B8), CRD (1C11, 1D8) and KNG (4A7, 4C10) domains of ROR1 ECD; induce apoptosis of patient-derived CLL cells | 253 |
| Cirmtuzumab (UC-961) | mAb | Inhibits WNT5a-induced activation of RAC1 | 288 |
| ROR1-CAR | CAR | ROR1-specific CAR generated based on a mAb that binds to the ECD of ROR1; T cells transduced with ROR1–CAR selectively lyse ROR1-overexpressing cancer cells | 289 |
| RYK | |||
| RWD1 | mAb | Binds to WIF domain of ECD; inhibits WNT5A-induced signalling and neurite outgrowth | 290 |
| TRIB2 | |||
| Afatinib | Small molecule | Irreversible ATP-competitive inhibitor of EGFR and HER2; forms covalent adduct with Cys96 in TRIB2; destabilizes TRIB2 in vitro and induces its degradation in cells | 233 |
| Neratinib, osimertinib | Small molecule | Irreversible ATP-competitive inhibitors of EGFR and HER2; destabilize TRIB2 in vitro | 233 |
| Lapatinib, TAK-285, GW693881A | Small molecule | Reversible ATP-competitive inhibitors of EGFR and HER2; stabilize TRIB2 in vitro | 233 |
| GW804482X | Small molecule | Reversible ATP-competitive inhibitor of PLK; destabilizes TRIB2 in vitro | 233 |
| TYK2 JH2 | |||
| Compound 1, BMS-066 | Small molecule | ATP-competitive inhibitor that blocks TYK2-mediated signalling through IL-23R in T cells | 200 |
| Compound 35 | Small molecule | ATP-competitive inhibitor that blocks TYK2-mediated signalling through IL-23R in T cells with greater selectivity and metabolic stability than compound 1 | 201 |
| BMS-986165 | Small molecule | ATP-competitive inhibitor that blocks TYK2-mediated signalling through IL-12, IL-23 and type I interferon signalling | 202 |
ADC, antibody–drug conjugate; ADCC, antibody-dependent cell-mediated cytotoxicity; CAR, chimeric antigen receptor; CDK, cyclin-dependent kinase; CLL, chronic lymphocytic leukaemia; CRD, cysteine-rich domain; DFG, Asp-Phe-Gly; ECD, extracellular domain; EGFR, epidermal growth factor receptor; ER, endoplasmic reticulum; Fc, crystallizable fragment of an antibody; HER, human epidermal growth factor receptor; IL-23R, interleukin-23 receptor; JAK, Janus kinase; JH, JAK homology; KNG, kringle; KSR, kinase suppressor of RAS; mAb, monoclonal antibody; MET, hepatocyte growth factor; MLKL, mixed lineage kinase domain-like protein; PTK7, protein tyrosine kinase 7; RIPK1, serine/threonine-protein kinase 1; RYK, receptor-like tyrosine kinase; TRIB2, Tribbles homologue 2; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor; WIF, WNT-inhibitory factor.