QuestionIs anti-programmed cell death 1 therapy effective and safe as first-line therapy in patients with advanced melanoma predominantly of acral subtype?FindingsIn this phase 3 randomized clinical trial of 256 patients with advanced melanoma (160 acral subtype [62.7%]), toripalimab as first-line therapy significantly improved blinded independent central review-assessed progression-free survival compared with dacarbazine with an acceptable safety profile.MeaningToripalimab could be used as a new first-line treatment option for advanced melanoma, particularly where acral cutaneous melanoma is the predominant subtype. ImportanceProgrammed cell death 1 (PD-1) inhibitors have been the standard first-line treatment for advanced melanoma; however, their clinical benefit in advanced melanoma predominantly of acral subtype remains unclear.ObjectiveTo evaluate the efficacy and safety of toripalimab (a PD-1 inhibitor) vs dacarbazine as the first-line treatment in advanced melanoma predominantly of acral subtype.Design, Setting, and ParticipantsThis multicenter, open-label, positive-control phase 3 randomized clinical trial enrolled patients with advanced melanoma from January 22, 2018, to July 12, 2023. Eligible patients had histologically confirmed stage III or IV melanoma and no prior systemic therapy for advanced melanoma. Data were analyzed from September 23 to November 27, 2023.InterventionPatients were randomized (1:1) to receive toripalimab, 240 mg, every 2 weeks for up to 2 years, or dacarbazine, 1000 mg/m2, every 3 weeks until disease progression or intolerable toxic effects. Patients in the dacarbazine group were allowed to receive toripalimab after radiographic disease progression.Main Outcomes and MeasuresProgression-free survival (PFS) assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors, version 1.1.ResultsThe analysis included 256 patients (median [range] age, 58 [18-85] years; 113 females [44.3%] and 142 males [55.7%]), among whom 160 participants (62.7%) had acral melanoma; 127 were randomized to receive toripalimab and 128 to dacarbazine (1 patient was excluded for Good Clinical Practice violation). The median (range) follow-up period was 11.8 (0.1-62.5) months. Toripalimab significantly reduced the risk of disease progression or death by 29.2% (hazard ratio, 0.71; 95% CI, 0.53-0.95; P = .02) compared with dacarbazine as assessed by BICR . Consistent PFS benefit was observed in most predefined subgroups, including patients with acral subtype. The BICR-assessed objective response rate of 11.0% (95% CI, 6.2%-17.8%) vs 8.6% (95% CI, 4.4%-14.9%), and the median duration of response of 13.8 (95% CI, 5.9-not evaluable) months vs 6.9 (95% CI, 3.8-not evaluable) months, respectively, also favored toripalimab over dacarbazine. Grade 3 or worse treatment-related adverse events occurred in 36 patients (28.3%) receiving toripalimab, with the most common (>= 3%) being increased lipase (11 patients [8.7%]), anemia (5 patients [3.9%]), increased gamma-glutamyltransferase (4 patients [3.1%]), hyponatremia (4 patients [3.1%]), and increased blood triglycerides (4 patients [3.1%]).Conclusions and RelevanceThis phase 3 randomized clinical trial found that as a first-line treatment for advanced melanoma predominantly of acral subtype, toripalimab showed a significant PFS benefit over dacarbazine and an acceptable safety profile.Trial RegistrationClinicalTrials.gov Identifier: NCT03430297 This randomized clinical trial evaluates the efficacy and safety of toripalimab vs dacarbazine as the first-line treatment in advanced melanoma predominantly of acral subtype.

Importance:Programmed cell death 1 (PD-1) inhibitors have been the standard first-line treatment for advanced melanoma; however, their clinical benefit in advanced melanoma predominantly of acral subtype remains unclear. Objective:To evaluate the efficacy and safety of toripalimab (a PD-1 inhibitor) vs dacarbazine as the first-line treatment in advanced melanoma predominantly of acral subtype. Design, Setting, and Participants:This multicenter, open-label, positive-control phase 3 randomized clinical trial enrolled patients with advanced melanoma from January 22, 2018, to July 12, 2023. Eligible patients had histologically confirmed stage III or IV melanoma and no prior systemic therapy for advanced melanoma. Data were analyzed from September 23 to November 27, 2023. Intervention:Patients were randomized (1:1) to receive toripalimab, 240 mg, every 2 weeks for up to 2 years, or dacarbazine, 1000 mg/m2, every 3 weeks until disease progression or intolerable toxic effects. Patients in the dacarbazine group were allowed to receive toripalimab after radiographic disease progression. Main Outcomes and Measures:Progression-free survival (PFS) assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors, version 1.1. Results:The analysis included 256 patients (median [range] age, 58 [18-85] years; 113 females [44.3%] and 142 males [55.7%]), among whom 160 participants (62.7%) had acral melanoma; 127 were randomized to receive toripalimab and 128 to dacarbazine (1 patient was excluded for Good Clinical Practice violation). The median (range) follow-up period was 11.8 (0.1-62.5) months. Toripalimab significantly reduced the risk of disease progression or death by 29.2% (hazard ratio, 0.71; 95% CI, 0.53-0.95; P = .02) compared with dacarbazine as assessed by BICR . Consistent PFS benefit was observed in most predefined subgroups, including patients with acral subtype. The BICR-assessed objective response rate of 11.0% (95% CI, 6.2%-17.8%) vs 8.6% (95% CI, 4.4%-14.9%), and the median duration of response of 13.8 (95% CI, 5.9-not evaluable) months vs 6.9 (95% CI, 3.8-not evaluable) months, respectively, also favored toripalimab over dacarbazine. Grade 3 or worse treatment-related adverse events occurred in 36 patients (28.3%) receiving toripalimab, with the most common (≥3%) being increased lipase (11 patients [8.7%]), anemia (5 patients [3.9%]), increased γ-glutamyltransferase (4 patients [3.1%]), hyponatremia (4 patients [3.1%]), and increased blood triglycerides (4 patients [3.1%]). Conclusions and Relevance:This phase 3 randomized clinical trial found that as a first-line treatment for advanced melanoma predominantly of acral subtype, toripalimab showed a significant PFS benefit over dacarbazine and an acceptable safety profile. Trial Registration:ClinicalTrials.gov Identifier: NCT03430297.

TPS9594 Background: Although several immune checkpoint inhibitors have been approved for advanced melanoma, there remain significant unmet clinical needs, particularly for immune-cold subtypes such as mucosal and acral melanoma, which are frequently observed in Chinese patients (pts). IBI363 targets and activates tumor-specific T cells that express both PD-1 and IL-2Rα, leading to enhanced antitumor activity and reduced toxicity. Previous phase 1 studies of IBI363 reported manageable safety profiles with encouraging efficacy in advanced melanoma (2024 ASCO Annual Meeting [9562], ESMO Virtual Plenary [VP4-2024], SITC [1502]). Here, we present the trial in progress of a phase 2 study evaluating efficacy and safety of IBI363 monotherapy versus pembrolizumab in mucosal and acral melanoma. Methods: This multicenter, randomized, controlled, open-label, phase 2 study planned to enroll 180 pts. Main inclusion criteria are: 1) locally advanced unresectable or metastatic mucosal or acral melanoma; 2) no previous systemic treatment for melanoma; 3) at least one measurable tumor lesion (target lesions) per RECIST v1.1. Pts with active or symptomatic central nervous system metastasis are excluded. Pts are randomized in a 1:1 ratio to receive IBI363 1 mg/kg Q2W (with a priming dose of 100 μg/kg administered 7 days before the full dose) in the experimental arm or to receive pembrolizumab 200 mg Q3W in the control arm. Stratification factors include subtype (mucosal vs acral) and M staging (M0 vs M1a(0)/M1b(0) vs M1a(1)/M1b(1) or M1c/M1d, (0) indicating baseline lactate dehydrogenase [LDH] ≤ upper limit normal [ULN] and (1) indicating baseline LDH > ULN). The primary endpoint is progression-free survival (PFS) assessed by independent radiological review committee (IRRC) per RECIST v1.1. The secondary endpoints include investigator-assessed PFS, IRRC-assessed and investigator-assessed objective response rate (ORR), disease control rate (DCR), duration of response (DoR), time to response (TTR) per RECIST v1.1, overall survival (OS), safety, pharmacokinetics (PK) and immunogenicity. No interim analysis is planned. A total of 118 PFS events among 180 pts is estimated to demonstrate the superior efficacy of IBI363 compared to the control, with a power of 90% (α=0.025, one-sided). Clinical trial information: CTR20250280 .

2502 Background: Despite great success of immunotherapy (IO) in advanced melanoma, there remains an unmet clinical need for resistant tumors. Pts with acral and mucosal melanomas show limited benefit from current therapies. IBI363, a first-in-class PD-1/IL-2 α-bias bispecific antibody fusion protein that blocks PD-1 and activates α-bias IL-2 to rejuvenate exhausted tumor-specific T cells, has shown encouraging efficacy in pts with advanced melanoma. Here, we present results of IBI363 from a phase 1 study (NCT05460767) and a phase 2 study (NCT06081920) of pts with IO-treated, advanced acral and mucosal melanoma. Methods: Eligible pts with IO-treated advanced acral and mucosal melanoma were enrolled. IBI363 was administered intravenously at 0.1 mg/kg every week, 0.3/0.6/1 mg/kg every 2 weeks (Q2W), or 1/1.5/2/3 mg/kg every 3 weeks (Q3W). Primary endpoints for the phase 1 study were dose-limiting toxicity (DLT) and safety, and for the phase 2 study were safety and investigator-assessed objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and progression-free survival (PFS) according to RECIST v1.1. Results: As of December 6, 2024, 91 pts were enrolled across the phase 1 (n = 76) and phase 2 (n = 15) studies (male: 47%; median age: 57 years; Asian: 100%; ECOG PS 1: 66%; stage IV: 89%); 47 pts had acral melanoma and 44 had mucosal melanoma. Median follow-up time was 8.2 months. Median treatment duration was 13.4 weeks (range: 2.0-72.4). Treatment-emergent adverse events (TEAEs) occurred in 90/91 (98.9%) pts including 27 (29.7%) pts with grade ≥3 (≥G3) TEAEs. TEAEs led to treatment discontinuation in 3 (3.3%) pts, and 1 (1.1%) pt had a TEAE leading to death which was considered to be treatment-related (sepsis). Most common TEAEs were arthralgia (59.3%, with 4.4% ≥G3), rash (42.9%, with 3.3% ≥G3), and anemia (42.9%, with 2.2% ≥G3). Among all pts with at least one post-baseline tumor assessment (n = 87), 1 pt had a complete response, 22 had partial responses, 33 had stable disease, 31 had progressive disease. ORR was 26.4% (95%CI: 17.6-37.0) with 16 responses confirmed and 2 pts still waiting for confirmation; DCR was 64.4% (95%CI: 53.4-74.4). Among pts treated at 1mg/kg and above (n = 74), the ORR was 28.4% (95%CI: 18.5-40.1) and DCR was 68.9% (95%CI: 57.1-79.2). Patients treated at 1 mg/kg Q2W (n = 30) had median DOR 14.0 months with a median follow-up of 9.1 months and 50.0% events; the median PFS was 5.7 (95% CI, 3.6-6.7) months with a median follow-up of 11.0 months and 73.3% events. Conclusions: IBI363 showed encouraging efficacy in pts with IO-treated advanced acral and mucosal melanoma. The safety profile was acceptable and manageable. Further global clinical development of IBI363 in melanoma is ongoing. Clinical trial information: NCT05460767 and NCT06081920 .

9553 Background: Results of the global, phase 3 LEAP-003 study, showed that lenvatinib (len) + pembrolizumab (pembro) significantly improved PFS compared with pembro alone in participants (pts) with predominantly cutaneous melanoma at the first interim analysis, but this benefit was not maintained with additional follow-up and there was no improvement in OS. Previous studies have shown that mucosal and acral melanomas, which are the predominant subtypes in Chinese patients, may benefit from combination therapy. Here, we present results for Chinese participants (pts) enrolled in the LEAP-003 global (NCT03820986) and China extension (NCT04889118) studies. Methods: Eligible pts were aged ≥18 y, had previously untreated unresectable stage III or IV melanoma, an ECOG PS of 0 or 1, and measurable disease per RECIST v1.1. Pts were randomly assigned 1:1 to len 20 mg or placebo (pbo) PO QD + pembro 200 mg IV Q3W for ≤2 y. Dual primary end points were PFS per RECIST v1.1 by BICR and OS. Secondary end points were ORR, DOR, and safety. Results: 131 pts from China enrolled and received treatment (len + pembro, n = 64; pbo + pembro, n = 67). Median time from first dose to data cutoff (Jan 18, 2023) was 18.1 mo (range, 12.7-29.5). In the overall China subgroup, median PFS was 6.1 mo (95% CI, 4.1-8.1) for len + pembro vs 2.0 mo (95% CI, 2.0-2.1) for pbo + pembro (HR, 0.55; 95% CI, 0.37-0.81); 18-mo PFS was 20.0% vs 12.8%. Median OS was 19.9 mo (95% CI, 11.9-26.8) for len + pembro vs 17.0 mo (95% CI, 12.7-25.7) for pbo + pembro (HR, 0.93; 95% CI, 0.58-1.48); 18-mo OS was 53.4% vs 49.6%. ORR was 26.6% (95% CI, 16.3-39.1; 4 CR, 13 PR) for len + pembro vs 16.4% (95% CI, 8.5-27.5; 4 CR, 7 PR) for pbo + pembro; median DOR was 13.7 mo (range, 3.8-21.4) vs NR (range, 4.2-21.4+). Among 30 pts with mucosal melanoma, median PFS was 8.1 mo (95% CI, 5.9-12.4) for len + pembro (n = 16) vs 2.0 mo (95% CI, 1.9-4.1) for pbo + pembro (n = 14; HR, 0.44; 95% CI, 0.20-0.97); 12-mo PFS was 33.5% vs 21.4%. Median OS was 26.8 mo (95% CI, 10.6-NR) for len + pembro vs 14.3 mo (95% CI, 9.0-NR) for pbo + pembro (HR, 0.51; 95% CI, 0.17-1.55); 18-mo OS was 68.8% vs 49.0%. ORR among pts with mucosal melanoma was 50.0% (95% CI, 24.7-75.3; 1 CR, 7 PR) for len + pembro vs 7.1% (95% CI, 0.2-33.9; 1 PR) for pbo + pembro. Treatment-related AEs occurred in 96.9% in the len + pembro arm vs 97.0% in the pbo + pembro arm (grade 3-5: 62.5% vs 16.4%). One pt (1.5%) in the pbo + pembro arm died due to treatment-related immune-mediated lung disease. Conclusions: In Chinese pts, the efficacy and safety profile observed with len plus pembro vs pembro alone was consistent with the global population. Numerical improvements in PFS and ORR in the mucosal melanoma subtype treated with len + pembro were notable, although the data should be interpreted with caution due to the limited sample size. These results support first-line pembro monotherapy as a standard-of-care for this population. Clinical trial information: NCT03820986 , NCT04889118 .

Background:Numerous meta-analyses and clinical studies have shown that subtypes of immune cells are associated with the development of skin cancer, but it is not clear whether this association is causal or biased. Mendelian randomization (MR) analysis reduces the effect of confounding factors and improves the accuracy of the results when compared to traditional studies. Thus, in order to examine the causal relationship between various immune cell and skin cancer, this study employs two-sample MR. Methods:This study assesses the causal association between 731 immune cell characteristics and skin cancer using a two-sample Mendel randomization (MR) methodology. Multiple MR methods were used to bias and to derive reliable estimates of causality between instrumental variables and outcomes. Comprehensive sensitivity analyses were used to validate the stability, heterogeneity and horizontal multiplicity of the results. Results:We discovered that potential causal relationships between different types of immune cells and skin cancer disease. Specifically, one type of immune cell as potentially causal to malignant melanoma of skin (MM), eight different types of immune cells as potentially causal to basal cell carcinoma (BCC), four different types of immune cells as potentially causal to actinic keratosis (AK), and no different types of immune cells were found to have a potential causal association with squamous cell carcinoma（SCC）, with stability in all of the results. Conclusion:This study demonstrates the close connection between immune cells and skin cancer disease by genetic means, which enriches the current knowledge about the role of immune cells in skin cancer and also contributes to the design of therapeutic strategies from an immunological perspective.

In condensed matter physics, particularly in perovskite materials, the rotational motion of molecules and ions is associated with important issues such as ion conduction mechanism. Constrained Molecular Dynamics (MD) simulations offer a means to separate translational, vibrational, and rotational motions, enabling the independent study of their effects. In this study, we introduce a rotational and roto-translational constraint algorithm based on the Velocity Verlet integrator, which has been implemented into a homebrew version of the CP2K package. The MD results show that our program can selectively constrain the molecules and ions in the system and support long-time MD runs. The algorithm can help the future study of important rotation related dynamic problems in condensed matter systems.

Abstract A 50-year-old man experienced cough and bloody sputum for 1 month. CT detected a mass in the right lung. Staging 18F-FDG PET/CT revealed multiple hypermetabolic lesions in the lung, mediastinum, liver, and bones. Further physical examination revealed black patches in the skin covering most parts of the body, which presented at his birth and were growing very slowly, consistent with giant congenital melanocytic nevus. Pathology examination after biopsy of the lung demonstrated metastatic melanoma.

Objectives Lung cancer has been widely characterized through radiomics and artificial intelligence (AI). This review aims to summarize the published studies of AI based on positron emission tomography/computed tomography (PET/CT) radiomics in non-small-cell lung cancer (NSCLC). Materials and methods A comprehensive search of literature published between 2012 and 2022 was conducted on the PubMed database. There were no language or publication status restrictions on the search. About 127 articles in the search results were screened and gradually excluded according to the exclusion criteria. Finally, this review included 39 articles for analysis. Results Classification is conducted according to purposes and several studies were identified at each stage of disease:1) Cancer detection (n=8), 2) histology and stage of cancer (n=11), 3) metastases (n=6), 4) genotype (n=6), 5) treatment outcome and survival (n=8). There is a wide range of heterogeneity among studies due to differences in patient sources, evaluation criteria and workflow of radiomics. On the whole, most models show diagnostic performance comparable to or even better than experts, and the common problems are repeatability and clinical transformability. Conclusion AI-based PET/CT Radiomics play potential roles in NSCLC clinical management. However, there is still a long way to go before being translated into clinical application. Large-scale, multi-center, prospective research is the direction of future efforts, while we need to face the risk of repeatability of radiomics features and the limitation of access to large databases.

Different from surgery, chemical therapy, radio-therapy and target therapy, Chimeric antigen receptor-modified T (CAR-T) cells, a novel adoptive immunotherapy strategy, have been used successfully against both hematological tumors and solid tumors. Although several problems have reduced engineered CAR-T cell therapeutic outcomes in clinical trials for the treatment of thoracic malignancies, including the lack of specific antigens, an immunosuppressive tumor microenvironment, a low level of CAR-T cell infiltration into tumor tissues, off-target toxicity, and other safety issues, CAR-T cell treatment is still full of bright future. In this review, we outline the basic structure and characteristics of CAR-T cells among different period, summarize the common tumor-associated antigens in clinical trials of CAR-T cell therapy for thoracic malignancies, and point out the current challenges and new strategies, aiming to provide new ideas and approaches for preclinical experiments and clinical trials of CAR-T cell therapy for thoracic malignancies.

Aliphatic esters are essential constituents of biologically active compounds and versatile chemical intermediates for the synthesis of drugs. However, their preparation from readily available olefins remains challenging. Here, we report a strategy to access aliphatic esters from olefins through a photocatalyzed alkoxycarbonylation reaction. Alkyloxalyl chlorides, generated in situ from the corresponding alcohols and oxalyl chloride, are engaged as alkoxycarbonyl radical fragments under photoredox catalysis. This transformation tolerates a broad scope of electron-rich and electron-deficient olefins and provides the corresponding β-chloro esters in good yields. Additionally, a formal β-selective alkene alkoxycarbonylation is developed. Moreover, a variety of oxindole-3-acetates and furoindolines are prepared in good to excellent yields. A more concise formal synthesis of (±)-physovenine is accomplished as well. With these strategies, a wide range of natural-product-derived olefins and alkyloxalyl chlorides are also successfully employed.

An efficient and benign iron-catalyzed room-temperature method was developed for direct sequential C(sp3)-H/N-H annulation to construct pyrroloindole scaffolds. This strategy features cheap and readily available raw materials and mild room-temperature reaction conditions and provides a green and practical method for the one-pot rapid synthesis of a wide range of diversely functionalized pyrrolo[1,2-α]indoles.

Herein, we embarked on a structural optimization campaign aiming at the discovery of novel anticancer agents with our previously reported XL-6f as a lead compound. A library of 23 compounds has been synthesized based on the highly conserved active site of VEGFR-2. Several title compounds exhibited selective inhibitory activities against VEGFR-2, which also displayed selective anti-proliferation potency against HepG2 cell. All synthesized compounds were evaluated for anti-angiogenesis capability. Compound 7o showed the most potent anti-angiogenesis ability, the efficient cytotoxic activities (in vitro against HUVEC and HepG2 cell lines with IC50 values of 0.58 and 0.23 mu M, respectively). The molecular docking analysis revealed 7o is a Type-II inhibitor of VEGFR-2 kinase. In general, these results indicated these arylamide-5-anilinoquinazoline-8-nitro derivatives are promising inhibitors of VEGFR-2 for the potential treatment of anti-angiogenesis.

Herein, we have carried out a structural optimization campaign to discover the novel anti-tumor agents with our previously screened YQY-26 as the hit compound. A library of thirty-seven 6-amide-2-aryl benzoxazole/benzimidazole derivatives has been designed and synthesized based on the highly conserved active site of VEGFR-2. Several title compounds exhibited selective inhibitory activities against VEGFR-2 than EGFR kinases, which also displayed selective anti-proliferation potency against the HUVEC and HepG2 than the A549 and MDA-MB-231 cancer cell lines. The newly synthesized compounds were evaluated for anti-angiogenesis capability by chick chorioallantoic membrane (CAM) assay. Among them, compounds 9d showed the most potent anti-angiogenesis ability (79% inhibition at 10 nM/eggs), the efficient cytotoxic activities (in vitro against the HUVEC and HepG2 cell lines with IC50 values of 1.47 and 2.57 μM, respectively), and excellent VEGFR-2 kinase inhibition (IC50 = 0.051 μM). The molecular docking analysis revealed that compound 9d is a Type II inhibitor of VEGFR-2 kinase. These results indicated that the 6-amide-2-arylbenzoxazole and 6-amide-2-aryl benzimidazole derivatives are promising inhibitors of VEGFR-2 kinase for the potential treatment of anti-angiogenesis.

We embarked on a structural optimization campaign aimed at the discovery of novel anti-angiogenesis agents with previously reported imidazole kinase inhibitors as a lead compound. A library of 29 compounds was synthesized. Several title compounds exhibited selective inhibitory activities against vascular endothelial growth factor receptor 2 (VEGFR-2) over epidermal growth factor receptor (EGFR) kinase; these compounds also displayed selective and potent antiproliferative activity against three cancer cell lines. The newly synthesized compounds were evaluated for anti-angiogenesis activity by chick chorioallantoic membrane (CAM) assay. Among them, 1-(2-(2-chlorophenyl)benzo[d]oxazol-5-yl)-3-(4-(trifluoromethoxy)phenyl)urea (compound 5 n) showed the most potent anti-angiogenesis capacity, efficient cytotoxic activities (in vitro against human umbilical vein endothelial cells (HUVEC), H1975, A549, and HeLa cell lines, with respective IC50 values of 8.46, 1.40, 7.61, and 0.28 mu m), and an acceptable level of VEGFR-2 kinase inhibition (IC50=0.25 mu m). Molecular docking analysis revealed 5 n to be a type II inhibitor of VEGFR-2 kinase. In general, these results indicate that these 6-arylurea-2-arylbenzoxazole/benzimidazole derivatives are promising inhibitors of VEGFR-2 kinase for potential development into anti-angiogenesis drugs.

A novel series of benzylidene-succinimide derivatives were synthesized, characterized and evaluated for their cytotoxicities against HCT116, and SW480 cancer cells and NCM460 normal human cells. Their antiangiogenic capabilities were evaluated using a chick chorioallantoic membrane (CAM) assay. The compound, XCF-37b, was selected as the most potent antiangiogenic inhibitor with noncytotoxicity to evaluate the pharmacological effects on human umbilical vein endothelial cells (HUVECs) and cancer cells in vivo and in vitro. The results showed that XCF-37b inhibited HT29-cell colon tumor growth in vivo, without showing cytotoxicity against the five other cancer cell lines in vitro. Experiments confirmed that XCF-37b had obvious antiangiogenic activity by HUVEC migration and invasion and rat aortic ring angiogenesis ex vivo. Mechanism studies showed that XCF-37b inhibited the AKT/mTOR and VEGFR2 signaling pathways, as evidenced by decreased expressions of phosphor-AKT (p-AKT), p-mTOR, p-VEGFR2 (Tyr175), p-Src (Tyr416), p-FAK (Tyr925), and p-Erk1/2 (Thr202/Tyr204). Moreover, XCF-37b significantly decreased the protein expressions of matrix metalloproteinase-2 (MMP-2), MMP-9 and hypoxia-inducible factor-1α (HIF-1α). XCF-37b generally regulated angiogenic inhibition through several regulatory pathways, without significantly interfering with colorectal cancer cell growth.

A novel series of 1-(aryl aldehyd oxime) uracil derivatives were synthesized, characterized and evaluated for its inhibitory activity against thymidine phosphorylase. Among them, the compound 8d, 8e, 8f, 8g and 8l displayed potent thymidine phosphorylase inhibitory activities with the IC50 values ranging between 0.12 ± 0.05 and 7.2 ± 1.4 μM. And the compounds 8a, 8h, 8i, 8j, 8m, 8n, 8o, 8q, 8s, 8t and 8u (IC50 is from 10.7 to 39.9 μM) showed a good thymidine phosphorylase inhibition when compared to the standard 7DX and TPI. The most biologically active compound 8l was demonstrated to be a competition mode of enzyme inhibition. The Molecular docking analysis showed the interaction of these newly synthesized compounds at the active binding site of thymidine phosphorylase based on the experimental results. In general, these results indicated these compounds are promising inhibitors of thymidine phosphorylase for the potential treatment of anti-angiogenesis.

A novel series of 2-phenylquinoline-4-carboxamide derivatives was synthesized, characterized and evaluated for its antiproliferative activity against five cancer cell lines, Hela, SK-OV-3, HCT116, A549 and MDA-MB-468, and a normal human fetal lung fibroblastic cell line, MRC-5. Among them, compound 7b displayed potent cytotoxic activity in vitro against SK-OV-3 and HCT116 cell lines with IC50 values of 0.5 and 0.2μM, respectively. In general, the antiproliferative activity was correlated with the binding property of the colchicine binding site and inhibitory effect on tubulin polymerization. In addition, immunofluorescence and flow cytometry analysis revealed that selected compounds caused disruption of the mitotic spindle assembly and G2/M phase arrest of the cell cycle, which correlated with proliferation inhibitory activity. Molecular docking analysis demonstrated the interaction of 7b at the colchicine binding site of tubulin. These results indicate these compounds are promising inhibitors of tubulin polymerization for the potent treatment of cancer.

A novel water-soluble oral satraplatin/β-cyclodextrin inclusion complex was prepared and characterized with a variety of techniques. The inclusion complex showed much higher antitumor activity in vitro cytotoxicity test and in vivo antitumor test.