The mosquito Anopheles gambiae is the principal Afrotropical vector for human malaria. A central component of its vectorial capacity is the ability to maintain sufficient populations of adults. During both adult and preadult (larval) stages, the mosquitoes depend on the ability to recognize and respond to chemical cues that mediate feeding and survival. In this study, we used a behavioral assay to identify a range of odorant-specific responses of An. gambiae larvae that are dependent on the integrity of the larval antennae. Parallel molecular analyses have identified a subset of the An. gambiae odorant receptors (AgOrs) that are localized to discrete neurons within the larval antennae and facilitate odor-evoked responses in Xenopus oocytes that are consistent with the larval behavioral spectrum. These studies shed light on chemosensory-driven behaviors and represent molecular and cellular characterization of olfactory processes in mosquito larvae. These advances may ultimately enhance the development of vector control strategies, targeting olfactory pathways in larval-stage mosquitoes to reduce the catastrophic effects of malaria and other diseases.malaria ͉ olfaction ͉ signal transduction ͉ odorant receptors S ensitivity and the ability to respond to a wide range of olfactory cues are essential for many behavioral processes that mediate the vectorial capacity of Anopheles gambiae and other diseasecarrying mosquitoes (1). Although there is a growing body of knowledge of the adult An. gambiae olfactory system, there is a paucity of information as to the molecular and cellular basis of olfaction in larval stages, in which it may be of potential importance in disease control. Paradoxically, despite being one of the historically most successful strategies for mosquito control (2) and prevention of human malaria, the targeting of mosquito larvae or larval habitats around human dwellings is sparsely implemented in Africa and other malaria-endemic regions (3). Furthermore, the simplicity of insect larval olfactory systems makes them excellent models to study olfactory signal transduction and coding. Indeed, the arbovirus vector mosquito Aedes aegypti expresses 24 odorant receptor (OR) genes in the larval antenna, 15 of which are larval specific (4). Elegant work in the Drosophila melanogaster model has detailed larval behavioral responses and characterized 25 ORs that are expressed in 21 olfactory receptor neurons (ORNs) in each of the two dorsal organs, which constitute the olfactory apparatus of the fly larva (5-7).In this study, we designed and used a simple olfactory-based assay to carry out an initial characterization of An. gambiae larval behavioral responses to a range of natural and synthetic chemical stimuli. Consistent with olfactory function, ablation of the larval antennae specifically eliminated these behavioral responses, and molecular approaches identified a set of larval AgOrs, which were in some cases larval specific and the transcripts of which were mapped to a distinctive population of ORNs within th...

Members of the Culex pipens mosquito group including C. quinquefasciatus are responsible for the transmission of Bancroftian filarisis as well as West Nile Virus (WNV) in the United States. As is the case for other mosquitoes, the host preference of this disease vector relies on olfaction and accordingly mediated via G-protein coupled signal transduction pathways. Here, we identify and characterize CqOR7, the first candidate member of the odorant receptor gene family from C. quinquefasciatus. CqOR7 displays extremely high primary amino acid conservation with other apparent orthologs including AaOR7, from the Dengue virus vector mosquito Aedes aegypti, AgOR7 from the malaria vector Anopheles gambiae and DOr83b from the fruit fly Drosophila melanogaster that form an essential non-conventional odorant receptor sub-family. CqOR7 transcripts can be detected in adult chemosensory tissues and during several pre-adult stages of C. quinquefasciatus, and the CqOR7 protein is localized to characteristic olfactory tissues such as the antennae and maxillary palps as well as the proboscis, a typically gustatory appendage. These results suggest that CqOR7 and its orthologs are likely to play a role in the chemosensory processes of Culicine and other mosquitoes that underlie their vectorial capacity.

Objective: Cell division cycle 7 (CDC7), a receptor serine/threonine kinase which features high-affinity with protein DBF4, plays an important role in DNA replication and DNA damage response via MCM2 phosphorylation. CDC7 has been reported to be up-regulated by about 50% in various human cancers and is being investigated as a therapeutic target in clinical trials. The purpose of this study is to investigate the in-vitro and in-vivo antitumor activities of TQB3824, a small molecule of CDC7 kinase inhibitor, in preclinical models with CDC7 overexpression. Method: Kinase inhibition activities of TQB3824 were determined with CDC7/DBF4 kinase assays. Cellular anti-proliferative activities were evaluated in COLO205 cell line and NCI-H226 cell line, which features CDC7 overexpression and no CDC7 expression, respectively. Three CDX models, colorectal cancer COLO205/SW620 and pancreatic cancer CAPAN-1 with KRAS mutation, were used to test the efficacy of TQB-3824 in vivo. Result: TQB3824 showed potent activities in both kinase inhibition and COLO205 cell anti-proliferation, with IC50 of 2.9 nM and 14.5 nM, separately. In contrast, TQB3824 showed much weaker anti-proliferative activity in NCI H226 cells with IC50 of 8154 nM. TQB3824 displayed strong antitumor efficacy in CDC7 highly expressed colorectal cancer CDX model COLO205 (TGI = 77% @5 mpk, BID), SW620 CDX model (TGI = 100% @5 mpk, BID), and pancreatic cancer CAPAN-1 CDX model (TGI = 115% @6 mpk, BID). Conclusion: We have identified a novel potent CDC7 inhibitor TQB3824, which shows high antitumor efficacy in CDC7 overexpressed solid tumor models. TQB3824 represents a promising clinical candidate for treating solid tumors with high CDC7 expression. Citation Format: Gang Li, Xiquan Zhang, Ling Yang, Xin Tian, Zhong xiong, Lihong Hu, Yuanfeng xia, Chi-chung chan, Charles Z. Ding, Shuhui Chen. Preclinical candidate TQB3824, a small molecule inhibitor of CDC7, shows strong antitumor efficacy in colorectal and pancreatic tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1970.

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The G1 restriction point is critical for regulating the cell cycle and is controlled by the retinoblastoma protein (Rb) pathway (CDK4/6-cyclin D1-Rb-p16/ink4a). Selective CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib have been approved by US FDA as single agent or in combination with endocrine therapy to treat patients with HR+/Her2- breast cancer. Here, we disclose the preclinical development of CS3002 and its characterization as a novel CDK4/6 inhibitor with unique kinase inhibition spectrum. Similar to the three approved CDK4/6 inhibitors, CS3002 is highly selective for and potent against CDK 4 and 6, a feature that is expected to overcome the toxicity issues of pan-CDK inhibitors. Cell-based assays confirmed the biological activities of CS3002 by showing anti-proliferative effect, significant Rb phosphorylation inhibition, and G1 cell cycle arrest in a set of Rb-positive cancer lines. Furthermore, CS3002 showed excellent in vivo activity as a single agent, and in combinations with either endocrine therapy (fulvestrant) or PD-1 blockade (CS1003) in a set of tumor models, together with desirable ADME/PK and safety profile. CS3002 was further tested against 196 kinases in a Carna panel. In addition to CDK4 and CDK6, FLT3 and TRKA were also potently inhibited with IC50 values <50nM. To this end, CS3002 demonstrated high activity in cell lines harboring NTRK1 fusion that were otherwise insensitive to CDK4/6 inhibitors. Across a panel of 19 AML cell lines, CS3002 demonstrated a similar sensitivity profile to gilteritinib (an approved FLT-3 inhibitor), but overall higher sensitivity compared to palbociclib. Interestingly, when MCF-7 breast cancer cell line was treated continuously with CS3002 in vitro, the emergence of drug-resistance was much delayed compared to treatment with palbociclib or abemaciclib. Given the encouraging preclinical properties as well as the unique potential in allowing indication expansion and delaying drug resistance to CDK4/6 inhibition, CS3002 is selected for clinical exploration in a Phase 1 study for advanced solid tumors (NCT04162301). Citation Format: Juan Zhang, Liang Tang, Zhenhu Li, Liang Lu, Yuanwu Bao, Zhaoxiang Ren, Jingshu Ma, Yaling Huang, Zhaobing Xu, Yuanfeng Xia, Charles Z. Ding, Lihong Hu, Shuhui Chen, Archie N. Xie, Xinzhong Jon Wang. CS3002, a novel CDK4/6 inhibitor with unique kinase inhibition spectrum which may expand indications beyond breast cancer and delay acquired drug resistance [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4844.