PROTAC D16-M1P2
PROTAC D16-M1P2 is an orally active CRBN-mediated selective PKMYT1 PROTAC degrader, with a DC50 of 0.7 nM in CCNE1-amplified HCC1569 breast cancer cells. PROTAC D16-M1P2 induces PKMYT1 degradation via the ubiquitin-proteasome system, directly inhibits PKMYT1 kinase activity, suppresses Thr14 phosphorylation of CDK1, and depends on functional CRBN and ubiquitination-like modification processes. PROTAC D16-M1P2 can be used for the research of CCNE1-amplified breast cancer, FBXW7-mutated cholangiocarcinoma, and PPP2R1A-deficient cancers.
(Pink: PKMYT1 ligand (HY-180484); Blue: Cereblon E3 ligase ligand; Black: linker).
For research use only. We do not sell to patients.
- Formula: C43H45FN10O4
- Molecular Weight:784.88
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Storage:
Please store the product under the recommended conditions in the Certificate of Analysis.
To place orders, for customer services and technical support, please contact: MedChemExpress USA
Tel: 609-228-6898 E-mail: [email protected] [email protected]
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Biological Activity
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Chemical Information
- Purity & Documentation
- References
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Help & FAQs
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Biological Activity
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PKMYT1 0.7 nM (DC50) |
PKMYT1 7.6 nM (IC50) |
CDK1 |
PROTAC D16-M1P2 (100 μM (3-fold serial dilutions, 10 gradients); 15 min (compound + PKMYT1); 60 min (tracer addition); 60 min (GST-Tb addition)) potently binds purified recombinant human PKMYT1 with an IC50 range of 4.1-5.0 nM in a competitive HTRF binding assay[1].
PROTAC D16-M1P2 inhibits purified recombinant human PKMYT1 enzymatic activity with an IC50 of 7.6 nM in an ADP-Glo kinase assay[1].
PROTAC D16-M1P2 (10 min (compound + kinase); 60 min (kinase reaction with substrate and ATP)) shows over 50-fold selectivity for purified recombinant human PKMYT1 over BRAF, RAF1, and SRC, with IC50 values of 485.3 nM, 373.1 nM, and 398.5 nM respectively[1].
PROTAC D16-M1P2 (30 min (compound + cells); 2 h (tracer addition)) engages intracellular PKMYT1 in transiently transfected HEK293 cells with an EC50 of 12.0 nM in a NanoBRET assay[1].
PROTAC D16-M1P2 (1 µs) (in both R- and S-oxa-azaspirodecane linker configurations) selectively accommodates the PKMYT1-CRBN-M4 conformation, forming moderately stable ternary complexes with docking scores of -10.85 kcal/mol (R) and -10.70 kcal/mol (S) that maintain sustained ubiquitination accessibility over 1 µs MD simulations[3].
PROTAC D16-M1P2 (100 ns) has linker length distributions compatible with the productive PKMYT1-CRBN-M4 conformation, consistent with its potent PKMYT1 degradation activity (DC50 = 0.70 nM)[3].
PROTAC D16-M1P2 (0.01-1000 nM; 24 h) induces potent, dose-dependent PKMYT1 degradation (DC50 0.7 nM, Dmax 90%) and pCDK1 (Thr14) inhibition (IC50 9.0 nM) in CCNE1-amplified HCC1569 breast cancer cells after 24 h treatment[1].
PROTAC D16-M1P2 (1 nM; 100 nM; 2, 4, 8, 24 h) induces rapid, time-dependent PKMYT1 degradation and pCDK1(Thr14) inhibition in CCNE1-amplified HCC1569 breast cancer cells, with 100 nM treatment producing robust pathway suppression while 1 nM treatment only induces partial degradation without significant signaling inhibition[1].
PROTAC D16-M1P2 (100 nM; 24 h pretreatment; 0, 2, 4, 16, 24 h post-washout incubation) induces durable PKMYT1 degradation and pCDK1Thr14 inhibition in CCNE1-amplified HCC1569 breast cancer cells, with effects sustained for at least 24 h after compound washout[1].
PROTAC D16-M1P2 (0.1 μM; 24 h) mediates PKMYT1 degradation in CCNE1-amplified HCC1569 breast cancer cells via a ubiquitin-proteasome system-dependent mechanism requiring both PKMYT1 and CRBN binding[1].
PROTAC D16-M1P2 (10 nM; 100 nM; 8 h) exhibits high proteome-wide selectivity for PKMYT1 in CCNE1-amplified HCC1569 breast cancer cells, with PKMYT1 being the only significantly degraded protein after 8 h treatment at 10 nM or 100 nM[1].
PROTAC D16-M1P2 (7 days) inhibits proliferation of human tumor cell lines with CCNE1 amplification, FBXW7 mutation, or PPP2R1A loss with 12-fold selectivity over wild-type cell lines, with an average IC50 of 177 nM in biomarker-positive cells after 7 days of treatment[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:HCC1569 breast cancer cells (CCNE1-amplified)
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Concentration:0.02-1000 nM
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Incubation Time:24 h
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Result:Induced dose-dependent PKMYT1 degradation with a DC50 of 0.7 nM and a maximum degradation (Dmax) of 90%.
Inhibited pCDK1 (Thr14) with an IC50 of 9.0 nM, superior to other D16 diastereoisomers.
Showed a hook effect at concentrations above maximal degradation, where PKMYT1 degradation decreased but pCDK1 inhibition continued to increase.
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Cell Line:HCC1569 breast cancer cells (CCNE1-amplified)
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Concentration:1 nM; 100 nM
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Incubation Time:2, 4, 8, 24 h
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Result:At 100 nM, reduced PKMYT1 levels by over 80% within 4 h and reached maximal degradation at 24 h (faster than PKMYT1's natural half-life of 12.5 h).
At 100 nM, achieved over 50% pCDK1 (Thr14) inhibition after 4 h, sustained for at least 24 h.
At 1 nM, induced ~60% PKMYT1 degradation after 8-24 h but did not produce significant pCDK1 (Thr14) inhibition.
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Cell Line:HCC1569 breast cancer cells (CCNE1-amplified)
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Concentration:0.1 μM D16-M1P2; 0.3, 1 μM MLN-4924; 0.1, 1 μM MG-132; 3, 10 μM pomalidomide; 0.1 μM compound 4
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Incubation Time:24 h
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Result:PKMYT1 degradation induced by D16-M1P2 was completely abolished in the presence of MG-132, MLN-4924, pomalidomide, or compound 4.
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Cell Line:HCC1569 breast cancer cells (CCNE1-amplified)
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Concentration:100 nM
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Incubation Time:24 h pretreatment; 0, 2, 4, 16, 24 h post-washout incubation
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Result:PKMYT1 degradation and pCDK1 (Thr14) inhibition were maintained for at least 24 h post-washout.
Showed sustained effects in contrast to reference inhibitor RP-6306 whose inhibitory effect reversed within 2 h.
| Species | Dose | Route | CLplasma | Vdss | T1/2 | Cmax | AUClast | Bioavailability |
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| Mice[1] | 1 mg/kg | i.v. | 80.2 mL/min/kg | 6.6 L/kg | / | / | / | / |
| Mice[1] | 40 mg/kg | p.o. | / | / | 3.2 h | 1181 ng/mL | 7436 ng·h/mL | 91.3 % |
| Rat[1] | 1 mg/kg | i.v. | 17.6 mL/min/kg | 3.7 L/kg | / | / | / | / |
| Rat[1] | 20 mg/kg | p.o. | / | / | 7.7 h | 2269 ng/mL | 29851 ng·h/mL | 166.5 % |
| Dog[1] | 1 mg/kg | i.v. | 7.2 mL/min/kg | 3.3 L/kg | / | / | / | / |
| Dog[1] | 5 mg/kg | p.o. | / | / | 6.3 h | 583 ng/mL | 7461 ng·h/mL | 67.9 % |
| Monkey[1] | 1 mg/kg | i.v. | 19.3 mL/min/kg | 5.1 L/kg | / | / | / | / |
| Monkey[1] | 10 mg/kg | p.o. | / | / | 10.9 h | 144 ng/mL | 1721 ng·h/mL | 20.5 % |
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:NOD.CB17-Prkdcscid/NcrCrl (female, 6-8 weeks old, ~23-26 g)[1]
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Dosage:40 mg/kg; 120 mg/kg
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Administration:p.o.; twice daily; 21 days
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Result:Achieved 35.1% tumor growth inhibition (TGI) at 40 mg/kg.
Achieved 66.4% TGI at 120 mg/kg.
Induced ~65% PKMYT1 degradation and ~45% inhibition of pCDK1 (T14) at 8 hours post-last 40 mg/kg dose.
Induced ~75% PKMYT1 degradation and ~70% inhibition of pCDK1 (T14) at 8 hours post-last 120 mg/kg dose.
Induced ~55% PKMYT1 degradation and ~30% inhibition of pCDK1 (T14) at 24 hours post-last 40 mg/kg dose.
Induced ~70% PKMYT1 degradation and ~55% inhibition of pCDK1 (T14) at 24 hours post-last 120 mg/kg dose.
Observed a significant positive correlation (r = 0.82, p = 0.001) between PKMYT1 degradation and pCDK1 (T14) inhibition.
Chemical Information
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Molecular Weight 784.88
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Formula C43H45FN10O4
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SMILES
N#CC1=[C@]([C@](C(C)=C(C=C2)O)=C2C)C=NC3=C1C=C(N3)C4=CN=C(N5CCC6(CC(N7CCN(C8=C(F)C=C(NC9CCC(NC9=O)=O)C=C8)CC7)CO6)CC5)N=C4
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Shipping
Room temperature in continental US; may vary elsewhere.
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Storage
Please store the product under the recommended conditions in the Certificate of Analysis.
Purity & Documentation
References
[1]. Wang Y, et al. Discovery of a bifunctional PKMYT1-targeting PROTAC empowered by AI-generation. Nature communications. 2025 Nov 28;16(1):10759. [Content Brief]
[2]. Li L, et al. PKMYT1 in Cancer: Beyond Cell Cycle Checkpoints to Context-Dependent Therapeutic Vulnerability. Genes, chromosomes & cancer. 2026 Jul;65(7):e70151. [Content Brief]
[3]. Nassar H, et al. Computational mapping of productive POI-E3 ligase conformations to guide de novo degrader design: application to WEE1 and PKMYT1 PROTACs. Journal of cheminformatics. 2026 Jul 24;18(1):103. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
PROTAC D16-M1P2 Related Classifications
HY-180485 Related Classifications
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