Orally bioavailable BTK PROTAC active against wild-type and C481 mutant BTKs in human lymphoma CDX mouse models.

Bruton tyrosine kinase (BTK) is an important signaling hub that activates the B-cell receptor (BCR) signaling cascade. BCR activation can contribute to the growth and survival of B-cell lymphoma or leukemia. The inhibition of the BCR signaling pathway is critical for blocking downstream events and treating B-cell lymphomas. Herein, we report potent and orally available proteolysis-targeting chimeras (PROTACs) that target BTK to inactivate BCR signaling. Of the PROTACs tested, UBX-382 showed superior degradation activity for wild-type (WT) and mutant BTK proteins in a single-digit nanomolar range of half-maximal degradation concentration in diffuse large B-cell lymphoma cell line. UBX-382 was effective on 7 out of 8 known BTK mutants in in vitro experiments and was highly effective in inhibiting tumor growth in murine xenograft models harboring WT or C481S mutant BTK-expressing TMD-8 cells over ibrutinib, ARQ-531, and MT-802. Remarkably, oral dosing of UBX-382 for <2 weeks led to complete tumor regression in 3 and 10 mg/kg groups in murine xenograft models. UBX-382 also provoked the cell type-dependent and selective degradation of cereblon neosubstrates in various hematological cancer cells. These results suggest that UBX-382 treatment is a promising therapeutic strategy for B-cell-related blood cancers with improved efficacy and diverse applicability.

Tomato ARPC1 regulates trichome morphology and density and terpene biosynthesis.

MAIN CONCLUSION: Based on transcriptomic analysis of wild-type and mutant tomato plants, ARPC1 was found to be important for trichome formation and development and it plays a key role in terpene synthesis. Trichomes are protruding epidermal cells in plant species. They function as the first defense layer against biotic and abiotic stresses. Despite the essential role of tomato trichomes in defense against herbivores, the understanding of their development is still incomplete. Therefore, the aim of this study was to identify genes involved in trichome formation and morphology and terpene synthesis, using transcriptomic techniques. To achieve this, we examined leaf morphology and compared the expression levels of some putative genes involved in trichome formation between wild-type (WT) and hairless-3 (hl-3) tomato mutant. The hl-3 plants displayed swollen and distorted trichomes and reduced trichome density (type I and IV) and terpene synthesis compared with that of the WT plants. Gene expression analysis showed that Actin-Related Protein Component1 (ARPC1) was expressed more highly in the WT than in the hl-3 mutant, indicating its critical role in trichome morphology and density. Additionally, the expression of MYC1 and several terpene synthase genes (TPS9, 12, 20), which are involved in type VI trichome initiation and terpene synthesis, was lower in the hl-3 mutant than in the WT plants. Moreover, transformation of the hl-3 mutant with WT ARPC1 restored normal trichome structure and density, and terpene synthesis. Structural and amino acid sequence analysis showed that there was a missplicing mutation in the hl-3 mutant, which was responsible for the abnormal trichome structure and density, and impaired terpene synthesis. Overall, the findings of this study demonstrated that ARPC1 is involved in regulating trichome structure and terpene synthesis in tomato.

Expansion of Human Megakaryocyte-Lineage Progeny via Aryl Hydrocarbon Receptor Antagonism with CH223191.

Aryl hydrocarbon receptor (AhR) antagonism is known to expand human hematopoietic stem cells (HSCs). However, its regulatory effect on the lineage-skewed differentiation of HSCs has not been sufficiently studied. Here, we investigate the effect of the AhR-selective antagonist CH223191 on the regulation of HSC differentiation. Consistent with the well-known effects of AhR antagonists, CH223191 treatment increase phenotypic HSCs (Lin-CD34 + CD38-CD90 + CD45RA-) and preserves their functionality. On the other hand, CH223191 leads to an overall expansion of megakaryocyte (MK)-lineage populations, such as MK progenitors (MKps, CD34 + CD41 +), immature MKs (CD41 + CD42b-), and mature MKs (CD41 + CD42b +), and it also activates MK/platelet-associated signaling pathways. Furthermore, CH223191 expands MKps, mature MKs, and p-selectin (CD62p)-positive platelet-like particles in immune thrombocytopenia (ITP) patient bone marrow (BM). These results highlight the numerical expansion of human MK-lineage progeny through AhR antagonism with CH223191. This approach using CH2231291 may be applicable in the development of auxiliary treatment regimens for patients with abnormal thrombopoiesis.