KIN-8194 / Dana-Farber Cancer Institute - LARVOL DELTA

Discovery and Characterization of a First-In-Class HCK/BTK PROTAC DFCI-002-06 for the Treatment of MYD88 Mutated B Cell Malignancies. (PubMed, J Med Chem) - "Building on our previously developed dual HCK/BTK inhibitor KIN-8194, we designed DFCI-002-06, a first-in-class proteolysis-targeting chimera (PROTAC) that potently and selectively degrades both kinases while retaining kinase inhibitory activity with improved selectivity versus KIN-8194. DFCI-002-06 induced enhanced apoptosis in MYD88Mut lymphoma cells and remained active against ibrutinib-resistant BTKCys481 variants...Preclinical safety studies showed a favorable profile, including a negative Ames test, no hERG inhibition at relevant concentrations, and excellent tolerability in a 21 day rat toxicity study. DFCI-002-06 represents a rational dual-target degradation strategy for MYD88Mut lymphomas."

Journal • Hematological Malignancies • Lymphoma • Oncology • Targeted Protein Degradation • HCK • MYD88

Aberrant Expression of Spliced WNK2 Is an Early Event in MYD88 Mutated WM That Activates ERK1/2 and Supports Tumor Growth (ASH 2023) - "ERK1/2 is a pro-survival signal in WM; its activation is accompanied by the release of inflammatory cytokines and can mediate ibrutinib resistance...Upon treatment with the highly potent dual HCK/BTK inhibitor KIN-8194, we observed dose-dependent decreases in phosphorylation levels of HCK, BTK, and ERK and total levels of WNK2 in WNK2-PB4 overexpressing BCWM.1 and MWCL-1 cells versus vector control transduced cells... Taken together, our findings show a high selection pressure to aberrantly regulate WNK2 expression at an early stage of MYD88MUT WM with different evolution in CXCR4WT vs CXCR4MUT WM, thus suggesting a role for aberrantly spliced WNK2 in the oncogenesis of MYD88MUT WM. Overexpression of the aberrantly spliced WNK2-PB4 isoform in stable WM cell lines provided a proliferation advantage and led to ERK1/2 activation, which may be induced by the WNK2/HCK interaction."

Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Lymphoplasmacytic Lymphoma • Oncology • Solid Tumor • Waldenstrom Macroglobulinemia • CXCR4 • MAPK1 • MAPK3 • MYD88 • WNK2

Novel Protacs Demonstrate Dual Kinase Inhibition and Degradation of HCK and BTK, and Are Highly Active in MYD88 Mutated WM and ABC DLBCL Cells (ASH 2023) - "KIN-8194 blocked both HCK and BTK and was active both in vitro and in vivo in MYD88 mutated xenograft lymphoma models, including BTKCys481Ser ibrutinib resistant models. In these studies, we demonstrated the development and characterization of novel, dual HCK/BTK PROTACs that demonstrate potent and selective kinase inhibition and protein degradation of HCK and BTK. Importantly, the novel PROTACs showed enhanced apoptosis of MYD88 mutated WM and ABC DLBCL cells over the native kinase inhibitor KIN-8194 and sparing of healthy donor B- and T-cells. Lastly, novel HCK/BTK PROTACs exhibited high levels of bioavailability."

Chronic Lymphocytic Leukemia • CNS Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Lymphoplasmacytic Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Primary Central Nervous System Lymphoma • Targeted Protein Degradation • Waldenstrom Macroglobulinemia • ANXA5 • CRBN • MYD88 • SYK

Development and Characterization of Novel Dual HCK/BTK Bifunctional Protacs That Potently Inhibit Kinase Function and Demonstrate Robust in Vitro and In Vivo Degradation of Targets for the Treatment of MYD88-Mutated B-Cell Malignancies (ASH 2024) - "Our previous work led to the development of KIN-8194, a novel HCK/BTK kinase inhibitor that was highly active in vitro and in MYD88-mutated xenografts, including BTKC481S ibrutinib-resistant disease models. Both PROTACs showed robust bioavailability and degradation of HCK and BTK in murine TMD8 xenograft models as well as potent tumor suppression. These studies provide a framework for advancing bifunctional HCK/BTK PROTACs for treating MYD88-mutated lymphomas, including covalent BTK-inhibitor resistant disease carrying BTKCys481 mutations."

Preclinical • Chronic Lymphocytic Leukemia • CNS Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Lymphoplasmacytic Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Primary Central Nervous System Lymphoma • Targeted Protein Degradation • Waldenstrom Macroglobulinemia • CRBN • MYD88 • SYK

The dual HCK/BTK inhibitor KIN-8194 impairs growth and integrin-mediated adhesion of BTKi-resistant mantle cell lymphoma. (PubMed, Leukemia) - "Here, we show that KIN-8194, a dual inhibitor of BTK and HCK with in vivo activity against Myd88-L265P-driven diffuse large B-cell lymphoma and Waldenström Macroglobulinemia, has a potent growth inhibitory effect in MCL cell lines and primary MCL cells, irrespective of their sensitivity to BTKi (ibrutinib and acalabrutinib). Taken together, our data demonstrate that KIN-8194 inhibits growth and integrin-mediated adhesion of BTKi-sensitive MCL cells, as well as MCL cells with primary or acquired BTKi resistance. This renders KIN-8194 a promising novel treatment for MCL patients."

Journal • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Waldenstrom Macroglobulinemia • HCK • MYD88

The dual HCK/BTK inhibitor KIN-8194 impairs growth and integrin-mediated adhesion of BTKi-resistant mantle cell lymphoma (Leukemia, Nature) - "In addition, KIN-8194 inhibits integrin-mediated adhesion of BTKi-sensitive and insensitive MCL cells to fibronectin and stromal cells in an HCK-dependent manner. Finally, we show that MCL cells with acquired BTKi resistance retain their sensitivity to KIN-8194."

Preclinical • Mantle Cell Lymphoma

The dual HCK/BTK inhibitor KIN-8194 impairs growth and integrin-mediated adhesion of BTKi-resistant mantle cell lymphoma (Leukemia, Nature) - "In addition, KIN-8194 inhibits integrin-mediated adhesion of BTKi-sensitive and insensitive MCL cells to fibronectin and stromal cells in an HCK-dependent manner. Finally, we show that MCL cells with acquired BTKi resistance retain their sensitivity to KIN-8194."

Preclinical • Mantle Cell Lymphoma

Revealing the Role of the Arg and Lys in Shifting Paradigm from BTK Selective inhibition to the BTK/HCK Dual inhibition- Delving into the Inhibitory Activity of KIN-8194 Against BTK, and HCK in the Treatment of Mutated 〖BTK〗^Cys481 Waldenström Macroglobulinemia: A computational Approach. (PubMed, Anticancer Agents Med Chem) - "These structural insights provided a baseline for the understanding of the dual inhibitory activity of KIN-8194. Establishing the cruciality of the interactions between the KIN-8194 and Arg and Lys residues could guide the structure-based design of novel dual BTK/HCK inhibitors with improved therapeutic activities."

Journal • Hematological Disorders • Lymphoma • Lymphoplasmacytic Lymphoma • Waldenstrom Macroglobulinemia • HCK

A New Role for the SRC Family Member HCK As a Driver of BCR/SYK Signaling in MYD88 Mutated Lymphomas (ASH 2021) - "Consistent with these observations, treatment of primary MYD88 mutated WM LPCs cells with either A419259 or KIN-8194 also showed marked reduction in both p-HCK and p-SYK expression by PhosFlow analysis. Taken together, our findings show that SYK is activated by HCK in MYD88 Mut B-cell lymphomas cells; broaden the pro-survival signaling generated by aberrant HCK expression in response to MYD88 Mut ; and help further establish HCK as an important therapeutic target in MYD88 Mut B-cell lymphomas."

IO biomarker • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Waldenstrom Macroglobulinemia • CD19 • HCK • IRAK4 • LYN • MYD88 • SYK

"The HCK/BTK inhibitor KIN-8194 is active in MYD88-driven lymphomas and overcomes mutated BTKCys481 ibrutinib resistance https://t.co/rizjA4aDiV" (@BloodJournal)

Hematological Malignancies • Lymphoma • Oncology • MYD88

The HCK/BTK inhibitor KIN-8194 is active in MYD88 driven lymphomas and overcomes mutated BTKCys481 ibrutinib resistance. (PubMed, Blood) - "Activating mutations in MYD88 promote malignant cell growth and survival through HCK mediated BTK activation. The Bcl-2 inhibitor venetoclax enhanced the anti-tumor activity of KIN-8194 in BTKWT and BTKCys481Ser expressing MYD88 mutated lymphoma cells, and markedly reduced tumor growth and prolonged survival in mice with BTKCys481Ser expressing TMD-8 tumors treated with both drugs. The findings highlight the feasibility of targeting HCK, a key driver of mutated MYD88 pro-survival signaling, and provide a framework for the advancement of KIN-8194 for human studies in B-cell malignancies driven by HCK and BTK."

IO biomarker • Journal • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Oncology • MYD88