Anaplastic lymphoma kinase (ALK) Degrader

TRI-611 is a brain-penetrant, orally active molecular glue degrader targeting ALK. TRI-611 engages ALK via a distal degron, forms a ternary complex with CRBN, triggers ALK polyubiquitination and degradation, including TKI-resistant ALK fusion proteins. TRI-611 inhibits ALK downstream signaling pathways, induces anti-proliferative effects in ALK-positive cancer cells. TRI-611 induces regression of ALK-positive non-small cell lung cancer tumors in preclinical xenograft models. TRI-611 can be used for the research of ALK-positive non-small cell lung cancer, including TKI-refractory tumors and central nervous system metastases.

TL13-12 is a potent and selective ALK-PROTAC degrader and inhibits ALK activity with an IC₅₀ value of 0.69 nM. TL13-12 also prompts the degradation of additional kinases including Aurora A, FER, PTK2, and RPS6KA1 with IC₅₀ values of 13.5 nM, 5.74 nM, 18.4 nM, and 65 nM, respectively. TL13-12 is comprised of the conjugation of TAE684 (HY-10192) and the Cereblon ligand of Pomalidomide (HY-10984).

AP-1 is a PROTAC targeting anaplastic lymphoma kinase (ALK).

M4K3250 is a selective ALK2 PROTAC degrader with a pDC₅₀ of 7.9. M4K3250 induces the formation of a ternary complex between ALK2 and the E3 ubiquitin ligase CRBN, thereby causing ALK2 degradation and inhibiting ALK2 activity. M4K3250 exhibits cytotoxicity in glioblastoma cells. M4K3250 can be used in studies related to glioblastoma.

SIAIS001 is a CRBN-dependent ALK PROTAC degrader with a DC₅₀ of 3.9 nM. SIAIS001 induces ALK protein degradation via the ubiquitin-proteasome system. SIAIS001 induces G1/S phase cell cycle arrest and inhibits proliferation of cancer cells. SIAIS001 can be used for the research of anaplastic large-cell lymphomas.

ALK degrader 4 is a ALK HyT degrader with an IC₅₀ of 0.74 nM. ALK degrader 4 inhibits ALK kinase activity, increases the solvent-accessible surface area of hydrophobic residues near the ALK binding pocket, promotes ALK to form a partially unfolded conformation, and induces proteasomal degradation of ALK. ALK degrader 4 inhibits cancer cell proliferation. ALK degrader 4 can be used in research related to non-small cell lung cancer (ALK ligand: Brigatinib (HY-12857); hydrophobic tag: Norbornene (HY-W013021)).

MS99-β-Gal (Gal-MS99) is a galactose-modified NPM-ALK PROTAC degrader. MS99-β-Gal is only hydrolyzed by SA-β-gal and esterase in senescent cancer cells, releasing MS99, which specifically degrades the NPM-ALK fusion protein. MS99-β-Gal shows an IC₅₀ of 454.8 nM for aging Karpas 299 cells, significantly lower than that of normal Karpas 299 cells (IC₅₀ = 2.162 μM). MS99-β-Gal can be used for the research of cancer.

Pro-PEG3-BA is an EML4-ALK/EGFR PROTAC degrader, degrading EML4 ALK and EGFR mutant (L858R/T790M) with DC₅₀ values of 0.42 and 13.50 μM, respectively. Pro-PEG3-BA hinders proliferation and induces cell cycle arrest and apoptosis of NSCLC cells in vitro. Pro-PEG3-BA shows safety profile and decreases EML4-ALK protein via rewiring the ubiquitin- proteasome system in vivo. Pro-PEG3-BA can be used for non-small cell lung cancer research.

ALK degrader 2 is an orally active ALK HyT degrader that degrades EML4-ALK levels (DC₅₀ = 8 nM) and nucleophosmin (NPM)-ALK protein levels (DC₅₀ = 102 nM). ALK degrader 2 mediates ALK degradation via the Hsp70 chaperone system and ubiquitin-proteasome pathway. ALK degrader 2 induces significant S-phase cell cycle arrest and apoptosis in H3122 cells. ALK degrader 2 shows anti-tumor activity in mice bearing H3122 xenografts. ALK degrader 2 can be used for the study of non-small cell lung cancer (NSCLC). (Pink: ALK ligand (HY-W754809), Blue: Hyt (HY-W013021), Black: Linker (HY-Y1760), ALK ligand-linker conjugate (HY-175528)).

PROTAC ALK degrader-2 (B1-PEG) is an ALK degrader based on PROTACs, with the DC₅₀ of 45 nM in H3122 EML4-ALK DC50 (GSH+). PROTAC ALK degrader-2, through PEGylation, is engineered to self-organize into micelles in water and releases its active form in response to the tumor-specific high GSH environment.

ALK degrader 1 is a potent, hydrophobic tag (HyT)-based degrader that induces ubiquitin-proteasome system (UPS)-dependent EML4-ALK degradation (DC₅₀ = 0.13 μM). ALK degrader 1 demonstrates potent ALK degradation and antiproliferative effects in ALK-dependent cell lines, while showing minimal cytotoxicity in ALK fusion-negative cells. ALK degrader 1 triggers cell cycle arrest at the G0/G1 phase and stimulates apoptosis. ALK degrader 1 not only facilitates efficient degradation of the ALK protein but also disrupts key downstream effectors, including the STAT3 signaling axis. ALK degrader 1 mediates robust EML4-ALK degradation in vivo. ALK degrader 1 can be used for ALK-related diseases research.

WZH-17-002 is a WZH-15-125-based ALK PROTAC degrader with a DC₅₀ of 25 nM. WZH-17-002 enhances activities against Lorlatinib (HY-12215)-resistant ALK compound mutations. WZH-17-002 significantly reduces drug resistance in ALK-fusion non-small cell lung cancer (NSCLC) and inhibits tumor growth in EML4-ALK G1202R/L1196 M xenograft mice model. Pink: ALK ligand (HY-174314); Blue: CRBN ligase ligand (HY-14658); Black: linker (HY-174316)

PROTAC ALK degrader-1 (compound B1) is an ALK degrader based on PROTACs, with the DC₅₀ of 26 nM in H3122 EML4-ALK. PROTAC ALK degrader-1 can be used to synthesis PROTAC ALK degrader-2 (HY-161750) with superior bioavailability.

PROTAC ALK degrader-5 (Compound 17) is an efficient ALK PROTAC degrader, with its inhibitory effects on EML4-ALK and NPM-ALK being 27.4 nM and 116.5 nM respectively. PROTAC ALK degrader-5 exhibits potent anti-proliferative activity against H3122 and Karpas 299. PROTAC ALK degrader-5 effectively inhibits the phosphorylation of ALK and STAT3. PROTAC ALK degrader-5 can be used for the study of ALK-driven malignant tumors, such as human non-small cell lung cancer and anaplastic large cell lymphoma.

TD-004 is a potent ALK PROTAC degrader. TD-004 exhibits anti-ALK inhibitory activity with an IC₅₀ of 0.11 µM and selectively inhibits the proliferation of SU-DHL-1 and H3122 cells (ALK-positive cancer cells) with IC₅₀s of 0.058 µM and 0.28 µM, respectively. TD-004 induces degradation of ALK fusion proteins (NPM-ALK and EML4-ALK) via recruitment of the VHL E3 ligase and the proteasome pathway. TD-004 demonstrates significant tumor growth inhibition with a favorable safety profile in vivo. TD-004 can be used for the research of anaplastic large cell lymphoma and non-small cell lung cancer.

PROTAC ALK degrader-4 (Compound B8) is an ALK PROTAC degrader with a DC₅₀ of 445.25 nM. PROTAC ALK degrader-4 exhibits excellent anti-proliferative activity against NCI-H2228 and NCI-H3122. PROTAC ALK degrader-4 leads to a significant downregulation of 390 proteins, including IGF-1R and its downstream proteins such as ERK1/2 and STAT3. PROTAC ALK degrader-4 can be used for research on lung adenocarcinoma.

ALK degrader 3 is a ALK HyT degrader with an IC₅₀ of 1.2 nM. ALK degrader 3 inhibits ALK kinase activity, increases the solvent-accessible surface area of hydrophobic residues near the ALK binding pocket, promotes ALK to form a partially unfolded conformation, and drives ALK degradation via the proteasomal pathway. ALK degrader 3 inhibits the proliferation of tumor cells. ALK degrader 3 can be used for the research of non-small cell lung cancer. (ALK ligand: Brigatinib (HY-12857); hydrophobic tag: Tetraasterane (HY-W1139353)).

Lys-PEG3-BA is an EML4-ALK/EGFR PROTAC degrader with DC₅₀ values of 1.32 and 19.66 μM for H3122 (EML4-ALK) and H1975 (EGFR-L858R/T790M) cells, respectively. Lys-PEG3-BA hinders proliferation via rewiring the ubiquitin- proteasome system in vitro. Lys-PEG3-BA can be used for non-small cell lung cancer research.

PROTAC ALK degrader-3 (4B) is an orally active ALK degrader based on PROTACs, which can effectively induce persistent degradation of ALK fusion protein in Karpas 299 cells and strong inhibition of downstream pathways,IC₅₀ is 119.33 nM. PROTAC ALK degrader-3 exhibits antitumor activity. (Structure Note: PINK, ALK Inhibitor (HY-15656); Blue, E3 (HY-W023573); Black, linker (HY-168552)).

dALK-3 is an anaplastic lymphoma kinase (ALK) degrader. dALK-3 can effectively induce EML4-ALK degradation with a DC₅₀ of 0.182 μM. dALK-3 has good anti-proliferation activity against H3122 cells and can be used in the study of cancer.