Acta Pharmaceutica Sinica B

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Optimizing pyrazine-2-carboxamide derivatives as dual FLT3/HDAC inhibitors with enhanced pharmacokinetics and immunotherapeutic potential

Acta Pharmaceutica Sinica B. 2026, 16(8): 5383-5404.

Dual FLT3/HDAC inhibition represents a promising synergistic strategy to address tumor heterogeneity. Building upon our prior lead 25h, we developed novel 6-ethylpyrazine-2-carboxamide derivatives via systematic structural optimization to enhance pharmacokinetic properties and target selectivity. The optimized compound, CF-2-17, demonstrated potent dual inhibition of FLT3 (IC₅₀ = 1.1 nmol/L) and HDACs (IC₅₀ = 9.6 nmol/L), and exhibited a 27-fold selectivity for HDAC1 over HDAC6. Its improved physicochemical properties, including enhanced solubility and metabolic stability, translated into favorable plasma exposure in vivo. In the MOLM-13 (FLT3-ITD) xenograft model, oral administration of CF-2-17 showed antitumor efficacy comparable to combination therapy, without observable toxicity. CF-2-17 also exhibited antiproliferative activity against non-FLT3-ITD hematological malignancies and solid tumors, outperforming single-target agents. Furthermore, CF-2-17 effectively remodeled the tumor immune microenvironment through CD4⁺ T cell activation and IFN-γ elevation, achieving 87% tumor growth inhibition in LLC syngeneic models. Mechanistically, CF-2-17 reversed FLT3 blockade-induced DC dysfunction via activation of the NF-κB pathway, thereby reinstating DC-mediated antitumor immunity. This dual FLT3/HDAC inhibitor demonstrates synergistic epigenetic-immune modulation, offering a promising approach for heterogeneous malignancies.
Universal off-the-shelf TGF-β1-knockout whole-tumor cell vaccine overcomes immunotherapy resistance in pMMR/MSS tumors

Weixiao Yang, Zhexu Dong, Qi Xiong, Yushuang Ren, Lin Zhang, Yi Liu, Jiaqi Han, Tian Tian, Xiaolan Su, Gang Shi, Hongxin Deng

Acta Pharmaceutica Sinica B. 2026, 16(8): 5405-5423.

Mismatch repair-proficient (pMMR)/microsatellite-stable (MSS) tumors, representing the majority of solid cancers, remain largely unresponsive to immune checkpoint inhibitors, highlighting the urgent need for effective therapeutic strategies. Tumor cell vaccines, serving as delivery platforms for a broad repertoire of tumor antigens, hold potential for eliciting systemic antitumor immunity, yet their clinical efficacy has remained limited. Here, we developed Tβ1KO/PolyIC-Vac, an off-the-shelf therapeutic whole-tumor cell vaccine generated by CRISPR-Cas9-mediated TGF-β1 knockout and formulated with the TLR3 agonist Poly(I:C). In therapeutic vaccination models, subcutaneous vaccination significantly suppressed distal tumor growth, reduced lung metastases, and delayed spontaneous colorectal tumor progression. It also synergized with anti-PD-1 blockade, enhancing complete response rates and establishing baseline antitumor immunity. Mechanistically, knockout of tumor-derived TGF-β1 reprogrammed immunity by reducing MDSC accumulation to relieve local immunosuppression and activate dendritic cells in draining lymph nodes, while intrinsically triggering the tumor STAT1-IL-15 axis to enhance vaccine immunogenicity. Poly(I:C) further enhanced cross-presentation and adaptive immunity, conferring long-term cross-protection against heterologous tumors. Together, these findings establish Tβ1KO/PolyIC-Vac as a universal tumor vaccine platform capable of efficiently delivering a comprehensive repertoire of tumor antigens and eliciting robust, durable, and cross-protective tumor-specific immunity in immunotherapy-resistant pMMR/MSS tumors.
Preclinical evaluation of a novel tetrazine probe within a pretargeted delivery system for theranostics in HER2-positive tumor-bearing mice models

Acta Pharmaceutica Sinica B. 2026, 16(8): 5424-5438.

The approval of radionuclide therapy strategies in nuclear medicine has revolutionized the treatment landscape for patients with advanced malignancies. Due to significant HER2 overexpression in some solid tumors, radionuclide therapy targeting HER2 is a viable strategy. The traditional monoclonal antibody (mAb) direct radiolabelling system may lead to off-target radiation exposure. To address this limitation, we employed the established inverse-electron demand Diels-Alder (IEDDA)-based pretargeting strategy and designed a novel tetrazine probe. First, we identified the optimal targeting molecule (Pertuzumab) and optimal metabolic time (48 h) through micro-positron emission tomography/computed tomography (PET/CT) scans and biodistribution studies of [⁸⁹Zr]Zr-DFO-Per, [⁸⁹Zr]Zr-DFO-Per-F(ab')₂ and [⁸⁹Zr]Zr-DFO-Per-Fab. Next, TCO-Pertuzumab (TCO-Per) was administered to HER2-overexpressing SKOV3 tumor-bearing mice models, and after 48 h of circulation and clearance, a novel radiolabelled small molecule Tz ([¹³¹I]I-Tyr-d-peptide-PEG₁₁-Tz) was introduced. Through a series of in vivo studies, we observed prolonged retention of [¹³¹I]I-Tyr-d-peptide-PEG₁₁-Tz in SKOV3 tumors with rapid renal clearance, along with promising therapeutic efficacy. Our study demonstrates that the novel tetrazine probe within a pretargeting delivery system overcomes limitations of traditional strategies and shows promise for clinical translation.
Mussel-inspired biphasic microneedle patch for long-acting hypothyroidism treatment

Wen Zhang, Hanqing Liu, Jinxuan Hou, Kai Lei, Jiapeng Lei, Yinli Jin, Chuang Chen, Jianying Huang, Wei Li

Acta Pharmaceutica Sinica B. 2026, 16(8): 5439-5451.

Hypothyroidism, caused by insufficient thyroid hormone production or impaired responsiveness, is typically managed with lifelong daily oral levothyroxine sodium (LT₄). However, oral administration often suffers from variable gastrointestinal absorption and poor adherence. Here, we report a mussel-inspired biphasic microneedle (MN) patch integrating LT₄ microcrystals and a bioadhesive PDA-PAM hydrogel backing for sustained and patient-friendly hypothyroidism management. The biphasic MNs, composed of rapidly dissolving PVA/sucrose tips and a robust polystyrene base, efficiently deposit LT₄ microcrystals intradermally upon insertion, enabling gradual dissolution and sustained release. The hydrogel backing offered strong and flexible adhesion, ensuring reliable skin attachment during movement. In vitro, the patches exhibited first-order LT₄ release for 9 days. In hypothyroid rats, a single patch application maintained therapeutic plasma LT₄ concentrations for ∼6 days, with bioavailability comparable to intravenous injection. In a preliminary study in healthy volunteers (n= 13), placebo MN patches demonstrated high insertion efficiency, good short-term tolerability, and favorable user acceptability. While further studies are required to establish long-term safety and efficacy in patients with hypothyroidism, these findings support the feasibility of a minimally invasive, extended-interval LT₄ delivery strategy.
Targeted nanoparticles with triggered lysosomal escape enable anti-angiogenic immunotherapy for peritoneal metastatic colorectal cancer

Acta Pharmaceutica Sinica B. 2026, 16(8): 5452-5470.

Peritoneal metastatic colorectal cancer (PMC) is highly aggressive and resistant to anti-angiogenic monotherapy due to the angiogenesis-immunosuppression vicious cycle. This study develops dual-ligand modified nanoparticles (Reg/DMX@BPF NPs), co-loaded with the angiogenesis inhibitor regorafenib (Reg) and the stimulator of interferon genes (STING) agonist DMXAA (DMX). Reg prevents DMX aggregation as a molecular scaffold via π-π stacking. The folic acid (FA) and phenylboronic acid (PBA)-functionalized BSA (BPF) facilitates active tumor targeting and metastatic site enrichment. Upon internalization into lysosomes, the acidic pH triggers boronate ester bond formation between PBA and glycoproteins, inducing lysosomal disruption and efficient cytosolic release. In addition to STING activation, the BPF potently activates toll-like receptor 4 signaling, synergistically inducing M1 tumor-associated macrophages polarization and dendritic cells maturation. In vivo results demonstrate that Reg/DMX@BPF NPs synergistically inhibit tumor proliferation, normalize pathological vasculature, and reprogram the immunosuppressive microenvironment, which leads to reduced tumor burden and ascites. Collectively, the targeted lysosome-escape nanoparticles provide a novel strategy to overcome the poor efficacy of anti-angiogenic therapy against PMC.
Metal-drug coordinated nanozymes for ROS scavenging and Kupffer cell polarization to alleviate drug-induced liver injury

Xiayun Chen, Ziqi Liang, Lichong Lu, Zhouchuan Shao, Wenhui Tang, Yiqi Liu, Jianqiao Li, Baizhong Chen, Enping Lai, Guodong Zheng, Minyan Wei, Shiying Li

Acta Pharmaceutica Sinica B. 2026, 16(8): 5471-5486.

Drug-induced liver injury (DILI) is a predominant cause of acute liver failure, intricately associated with excessive reactive oxygen species (ROS) production and the activation of inflammatory cascades. In this study, a metal-drug coordinated nanozyme (M-dCNs) is rationally designed to simultaneously scavenge ROS and polarize Kupffer cells to alleviate DILI. Specifically, the coordination between ferric ions (Fe³⁺) and the complementary therapeutic agents of hesperetin (HST) and KPLH (KPLH1130) facilitates the formation of M-dCNs with uniform particle distribution and enhances structural stability. Notably, M-dCNs exhibits intrinsic antioxidant enzyme-mimetic activity, efficiently neutralizing intracellular ROS in damaged hepatocytes and thereby disrupting apoptosis-related signaling pathways. In parallel, M-dCNs synergistically reprograms hepatic macrophages toward an anti-inflammatory phenotype, leading to a marked reduction in pro-inflammatory cytokines such as tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β), and ultimately suppressing inflammatory cascades. In vivo studies demonstrate the hepatoprotective potential and therapeutic efficacy of M-dCNs in attenuating oxidative stress, reducing inflammatory cell infiltration, and restoring liver function. Collectively, this work presents a promising strategy for the treatment of DILI via the concurrent modulation of redox homeostasis and inflammatory microenvironment.
Expansion and functional diversification of terpene synthases shape volatile terpenoid landscape in Cannabis sativa

Acta Pharmaceutica Sinica B. 2026, 16(8): 5487-5503.

Terpenoids are key specialized metabolites in Cannabis sativa, shaping cultivar-specific aromas and potentially modulating cannabinoid effects. This study provided a comprehensive analysis of the terpene synthase (TPS) gene family in C. sativa, integrating haplotype-resolved genomic data, volatile terpene profiling, transcriptomics, and functional assays. The comprehensive volatile terpene profiling across 28 spatiotemporal samples spanning weekly developmental intervals and distinct maturity stages from six cultivars identified 227 cannabis volatile terpenes, including 88 monoterpenes and 139 sesquiterpenes, exhibiting distinct tissue, developmental stage, and cultivar-specific patterns. Comparative expression and co-expression network analysis revealed coordinated regulation between MEP/MVA pathways, TPS, and cannabinoid genes, underscoring a shared metabolic foundation. Genome annotation identified 41 full-length CsTPSDK genes, exhibiting extensive expansion and subfamily-specific clusters with structural divergence between haplotypes. Transcript profiling across developmental stages and cultivars distinguished a core set of highly expressed inflorescence-associated CsTPSs from genes exhibiting cultivar-specific regulation. Functional characterization of six previously unreported CsTPSDKs uncovered diverse mono- and sesquiterpene synthase activities, including unexpected substrate promiscuity across subfamilies. These findings deliver the most comprehensive functional annotation of the C. sativa TPS repertoire to date, elucidating the genetic and biochemical bases of terpene diversity and providing a foundation for targeted metabolic engineering and cultivar improvement.
From serendipity to rational design: Accelerating ionizable lipid discovery with LipidAI

Acta Pharmaceutica Sinica B. 2026, 16(8): 5504-5505.
Repositioning Ku70 unlocks cGAS-STING immunity in colorectal cancer

Acta Pharmaceutica Sinica B. 2026, 16(8): 5506-5507.
Editor Profiles: Guest Editors of the Special Column on Machine Learning in Drug Discovery

Acta Pharmaceutica Sinica B. 2026, 16(7): 3993-3993.

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