Tango Therapeutics (United States)

TNG908 is a potent, selective, and brain-penetrant MTA-cooperative PRMT5 inhibitor for the treatment of MTAP-deleted tumors. We describe here the chemical process development for the synthesis of TNG908 and the improvements that were achieved over the medicinal chemistry route with much higher yields and better purities. This commercial ready process is convergent, diastereoselective, safe, reproducible, and robust. A total of eight GMP batches have been successfully manufactured, resulting in high-purity API meeting all specifications.

There is growing recognition that a better understanding of how food systems respond to crises is critical to build and protect the food security of local populations. But rigorous and reliable methods to measure food system resilience are still missing. In this paper, we build on the current literature to develop an analytical framework aimed at assessing the resilience of food systems at local level. The novel element of the analysis lies in the levels at which resilience is considered. Combining the individual actor level with the notion of 'emergent properties' of food systems, we argue that the overall resilience of food system results from processes that take place – and need to be measured – at both individual and system levels. The framework is structured around three components: (i) the mapping of the actors and the local food system; (ii) the assessment of the resilience of these actors and that of the food system, and (iii) the outcomes of this resilience, assessed in term of local population’s food security. For each of those components, indicators are proposed and the ways to collect them are discussed. The paper then presents the types of analyses that would be necessary to complete to gain a better understanding of the situation regarding the resilience of the local food system under consideration, including the analysis of “positive deviance” among food system actors. The paper concludes with a series of reflections about the caveats and challenges that one may face when attempting to assess food system resilience.

Abstract There is a longstanding desire to take therapeutic advantage of dysregulated metabolic states in cancer. While it has been appreciated that lung tumors rewire their cellular metabolic networks to support unrestrained proliferation, metabolic vulnerabilities have largely not been explored in the context of specific onco-genotypes. This represents a major gap in our understanding of how different oncogenic drivers in non-small cell lung cancer (NSCLC) confer reliance on discrete metabolic networks to sustain tumor growth. The goals of this project are (1) to investigate metabolic dependencies in distinct molecular subtypes of lung cancer and (2) to elucidate how metabolic reprogramming drives resistance to targeted therapy. Using patient-derived cell culture models and tumor specimens collected from patients with ALK-positive (ALK+) NSCLC, we identified that lung tumors with ALK rearrangements harbor a unique metabolic signature marked by reliance on anabolic nucleotide pathways. A phosphoproteomic screen in ALK+ patient-derived cells identified a novel metabolic target of ALK signaling, GUK1, the only known enzyme responsible for GDP synthesis. We show that ALK binds to and phosphorylates GUK1 and that ALK-mediated GUK1 phosphorylation augments GDP/GTP nucleotide biosynthesis. Steady-state and tracing metabolomic studies demonstrate that ALK inhibition and GUK1 phosphomutant are epistatic in guanine nucleotide production. Molecular dynamic modeling suggests that phosphorylation of GUK1 alters the dynamics of active site closure to enhance substrate processivity and protects GUK1 from a non-catalytic confirmation. Introduction of phosphomutant GUK1 into ALK+ patient-derived cell lines results in decreased tumor proliferation in vitro and in vivo in xenograft models. Spatially resolved mass spectrometry imaging of tumor specimens from ALK+ patients demonstrates significant enrichment of guanine nucleotides in ALK+ and phospho-GUK1+ tumor cells. We identified that other oncogenic fusion proteins regulate GUK1 phosphorylation, highlighting the need to further characterize GUK1 as a metabolic liability in NSCLC. Furthermore, a subset of patient-derived cell lines with resistance to ALK tyrosine kinase inhibitors (TKIs) exhibits increased expression and phosphorylation of GUK1, indicating that regulation of this metabolic enzyme may play a role in mediating acquired resistance. We anticipate these studies will pave the way for the development of new therapeutic approaches by exploiting metabolic vulnerabilities in oncogene-driven lung cancers. Citation Format: Jaime Laurel Schneider, Kiran Kurmi, Ishita Dhiman, Roberta Colapietro, Shakchhi Joshi, Christian Johnson, Satoshi Yoda, Joao Paulo, Daniela Ruiz, Sylwia Stopka, Gerard Baquer, Jessica Lin, Kevin Haigis, Nathalie Agar, Steven Gygi, Aaron Hata, Marcia Haigis. GUK1 is a novel metabolic liability in oncogene-driven lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1156.

<div>Abstract<p>Synthetic lethality is a genetic interaction that results in cell death when two genetic deficiencies co-occur but not when either deficiency occurs alone, which can be co-opted for cancer therapeutics. Pairs of paralog genes are among the most straightforward potential synthetic–lethal interactions by virtue of their redundant functions. Here, we demonstrate a paralog-based synthetic lethality by targeting vaccinia-related kinase 1 (VRK1) in glioblastoma (GBM) deficient of VRK2, which is silenced by promoter methylation in approximately two thirds of GBM. Genetic knockdown of VRK1 in VRK2-null or <i>VRK2</i>-methylated cells resulted in decreased activity of the downstream substrate barrier to autointegration factor (BAF), a regulator of post-mitotic nuclear envelope formation. Reduced BAF activity following VRK1 knockdown caused nuclear lobulation, blebbing, and micronucleation, which subsequently resulted in G<sub>2</sub>–M arrest and DNA damage. The VRK1–VRK2 synthetic–lethal interaction was dependent on VRK1 kinase activity and was rescued by ectopic expression of VRK2. In <i>VRK2</i>-methylated GBM cell line–derived xenograft and patient-derived xenograft models, knockdown of VRK1 led to robust tumor growth inhibition. These results indicate that inhibiting VRK1 kinase activity could be a viable therapeutic strategy in <i>VRK2</i>-methylated GBM.</p>Significance:<p>A paralog synthetic–lethal interaction between VRK1 and VRK2 sensitizes <i>VRK2</i>-methylated glioblastoma to perturbation of VRK1 kinase activity, supporting VRK1 as a drug discovery target in this disease.</p></div>

Phage display enables the discovery of high-affinity binders. In phage display, one commonly uses traditional cloning methods to insert DNA into the coding region of one of the five capsid proteins. Here we describe the use of a new vector with kanamycin resistance and BsaI sites for the utilization of Golden Gate cloning into the N-terminus of mature protein III. We also describe the successful pentavalent display of six different inserts: the AviD-tag, the Z-domain of protein A, the Myc-tag, the ALFA nanobody, the BC2 nanobody, and the Flag-tag.

Abstract TP53 is the most mutated tumor suppressor gene in human cancers and is a master regulator of a wide array of cellular processes including but not limited to cell cycle progression and DNA damage response. Due to its diverse functions, therapies specifically exploit the vulnerabilities created by TP53 loss remained elusive. We established a panel of TP53 isogenic pair cell line models by knocking out TP53 from WT cell lines and observed that CHK1/2 inhibitor prexasertib showed preferential selectivity toward TP53 KO cell lines. To thoroughly examine additional nodes which could further exploit this selective sensitivity, we carried out genome-wide prexasertib anchor screen in A549 isogenic lines employing CRISPRn, CRISPRi and CRISPRa platforms. From these functional genomics screens, we identified that targeting the anti-folate pathway genes (TYMS, DHFR) showed selective synergy with prexasertib specifically in TP53 KO cells. Secondly, a panel of iron metabolism genes was identified across different CRISPR platforms as candidate TP53 context specific synthetic lethal hits synergize with prexasertib. And lastly, additional sub-context was identified which may inform patient selection strategy for prexasertib as single agent. Citation Format: Teng Teng, Stephen Paik, Shan-chuan Zhao, Ashley Choi, Steven A. Lombardo, Shangtao Liu, Samuel R. Meier, Yi Yu, Jannik N. Anderson, Alan Huang, Fang Li, Xuewen Pan. Isogenic CRISPR anchor screens identified actionable nodes to CHK1/2 inhibitor prexasertib in TP53 mutant cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P095.

ABSTRACT This study assessed how dietary diversity and food coping strategies differ by resilience and food insecurity status. Proportionate sampling technique was used to interview 3440 households in 18 districts of Zimbabwe. Results show that resilient and food secure households had good diet diversification and were less likely to adopt food coping strategies when compared to less resilient and food insecure ones. Adaptive and absorptive resilience capacities and income reduced the use of food coping strategies. Interventions that improve household resilience capacities and income should be promoted to reduce the use of food coping strategies.