A bibliometric analysis of follicular thyroid carcinoma: Current situation, hot spots, and global trends.

BACKGROUND: Follicular thyroid carcinoma (FTC), the second most prevalent thyroid cancer after papillary thyroid cancer (PTC), tends to metastasize distantly, leading to poorer outcomes. Despite substantial research, a holistic bibliometric analysis of FTC literature is lacking. This study aims to fill this gap by employing bibliometric methods to track FTC research evolution. METHODS: English FTC publications were systematically gathered from the Web of Science. Bibliometric analysis, using R, VOSviewer, CiteSpace, and Excel, synthesized data and explored global research trends and topics. RESULTS: From 2000 to 2023, 9086 authors from 1953 institutions across 75 countries contributed to 1776 papers in 491 academic journals on FTC. The last two decades have witnessed a steady increase in publications related to FTC, with the United States leading in terms of publication volume. The United States dominated both in publications and citations, with the National Cancer Institute and Sheue-Yann Cheng as leading contributors. The journal 'Thyroid' featured the most publications, while the 'Journal of Clinical Endocrinology and Metabolism' ranked highest in citation frequency. Research focused on gene expression analysis and preoperative diagnostics, with recent trends shifting toward prognosis management and machine learning due to advances in medical technology and increased health awareness. CONCLUSION: This comprehensive bibliometric analysis has mapped the landscape of FTC research, highlighting key contributors, institutions, and thematic trends. Current discourse predominantly revolves around genetic analysis, prognostic determinants, and preoperative diagnostics in FTC. This foundational work guides future FTC research, providing insights into its evolution.

Design, Synthesis, and Biological Evaluation of 2,4-Diaminopyrimidine Derivatives as Potent CDK7 Inhibitors.

Developing selective CDK7 inhibitors has emerged as a promising approach for cancer treatment owing to the critical role of CDK7 in cancer progression. Starting from BTX-A51, a CK1α inhibitor that also targets CDK7 and CDK9, we designed and synthesized a series of 2,4-diaminopyrimidine derivatives as potent CDK7 inhibitors. The representative compound, 22, displayed significant enzymatic inhibitory activity and demonstrated a remarkable selectivity profile against a panel of kinases, including seven CDK subtypes. Modeling studies and molecular dynamics simulations revealed that the sulfone group of 22 significantly enhanced the binding affinity, while the acetyl group contributed to the increased selectivity of CDK7 against CDK9. Compound 22 effectively inhibited the phosphorylation of RNA polymerase II and CDK2 and resulted in G1/S phase cell cycle arrest and apoptosis in MV4-11 cells. It appears to be a promising lead compound for the development of a CDK7 inhibitor for cancer therapy.

Discovery of CW-3308 as a Potent, Selective, and Orally Efficacious PROTAC Degrader of BRD9.

The bromodomain-containing protein BRD9 has emerged as an attractive therapeutic target. In the present study, we successfully identified a number of highly potent BRD9 degraders by using two different cereblon ligands developed in our laboratory. Further optimization led to the discovery of CW-3308 as a potent, selective, and orally bioavailable BRD9 degrader. It displayed degradation potency (DC50) < 10 nM and efficiency (Dmax) > 90% against BRD9 in the G401 rhabdoid tumor and HS-SY-II synovial sarcoma cell lines and had a high degradation selectivity over BRD7 and BRD4 proteins. CW-3308 achieved 91% of oral bioavailability in mice. A single oral dose efficiently reduced the BRD9 protein by >90% in the synovial sarcoma HS-SY-II xenograft tumor tissue. Oral administration effectively inhibited HS-SY-II xenograft tumor growth in mice. CW-3308 is a promising lead compound for further optimization and extensive evaluation for the treatment of synovial sarcoma, rhabdoid tumor, and other BRD9-dependent human diseases.

Incidental synchronous intrathyroidal parathyroid carcinomas and papillary thyroid microcarcinoma with compressive neck mass and primary hyperparathyroidism: case report and literature review.

BACKGROUND: Parathyroid carcinoma (PC) is a rare malignancy, often diagnosed incidentally through postoperative pathological examination. The occurrence of nodular goiter, intrathyroidal parathyroid carcinoma, contralateral parathyroid adenoma (PA), and papillary thyroid microcarcinoma (PTMC) is extremely uncommon, which prompted us to report our case experience. CASE PRESENTATION: We describe a 67-year-old male who presented with a cervical mass causing tracheal compression, which prompted him to seek medical advice. Based on preoperative auxiliary examination results from color Doppler ultrasound, SPECT parathyroid imaging, and blood tests, he was initially diagnosed with a suspected parathyroid adenoma and nodular goiter. Excision of the right lobe and isthmus of the thyroid, and left superior parathyroid gland was conducted, which were sent to intraoperative frozen pathological examination. During intraoperative observation, adhesion around the right thyroid lobe was discovered. Consequently, right central area lymph node dissection was performed due to suspicion of an aggressive malignant tumor. Histology and immunohistochemistry analysis revealed incidental intrathyroidal parathyroid carcinoma, contralateral parathyroid adenoma, classical papillary thyroid microcarcinoma, and nodular goiter. CONCLUSION: Parathyroid carcinoma should be highly suspected when extremely high levels of PTH and severe hypercalcemia are present, which cannot be simply explained by a preoperatively localized parathyroid adenoma, especially when suspicious malignant adhesion is found during intraoperative exploration. In cases where multifocal thyroid nodules are associated with increased uptake of 99Tc-sestamibi, the possibility of coexisting carcinomas should be considered, not only for thyroid malignancy but also for the potential presence of intrathyroidal parathyroid carcinoma.

Design, Synthesis, and Bioevaluation of Transcriptional Enhanced Assocciated Domain (TEAD) PROTAC Degraders.

Dysregulation of the Hippo pathway has been observed in various cancers. The transcription factor TEAD, together with its coactivators YAP/TAZ, plays a crucial role in regulating the transcriptional output of the Hippo pathway. Recently, extensive research has focused on small molecule inhibitors targeting TEAD, but studies on TEAD degraders are comparatively rare. In this study, we designed and synthesized a series of TEAD PROTACs by connecting a pan-TEAD inhibitor with the CRBN ligand thalidomide. A representative compound, 27, exhibited potent antiproliferative activity against NF2-deficient NCI-H226 cells. It dose-dependently induced TEAD degradation dependent on CRBN and proteasome system and decreased key YAP target genes CYR61 and CTGF expressions in NCI-H226 cells. Further degradation selectivity studies revealed that 27 exhibited more potent activity against TEAD2 compared to those of the other three family members in Flag-TEADs transfected 293T cells. Therefore, 27 may serve as a valuable tool for advancing biological studies related to TEAD2.

Design, synthesis, and bioevaluation of SOS1 PROTACs derived from pyrido[2,3-d]pyrimidin-7-one-based SOS1 inhibitor.

Oncogenic KRAS mutations drive an approximately 25 % of all human cancers. Son of Sevenless 1 (SOS1), a critical guanine nucleotide exchange factor, catalyzes the activation of KRAS. Targeting SOS1 degradation has engaged as a promising therapeutic strategy for KRAS-mutant cancers. Herein, we designed and synthesized a series of novel CRBN-recruiting SOS1 PROTACs using the pyrido[2,3-d]pyrimidin-7-one-based SOS1 inhibitor as the warhead. One representative compound 11o effectively induced the degradation of SOS1 in three different KRAS-mutant cancer cell lines with DC50 values ranging from 1.85 to 7.53 nM. Mechanism studies demonstrated that 11o-induced SOS1 degradation was dependent on CRBN and proteasome. Moreover, 11o inhibited the phosphorylation of ERK and displayed potent anti-proliferative activities against SW620, A549 and DLD-1 cells. Further optimization of 11o may provide us promising SOS1 degraders with favorable drug-like properties for developing new chemotherapies targeting KRAS-driven cancers.

Analysis of risk factors for lateral lymph node metastasis in T1 stage papillary thyroid carcinoma: a retrospective cohort study.

Background: The occurrence of cervical lymph node metastasis in T1 stage papillary thyroid carcinoma (PTC) is frequently observed. Notably, lateral lymph node metastasis (LLNM) emerges as a critical risk factor adversely affecting prognostic outcomes in PTC. The primary aim of this investigation was to delineate the risk factors associated with LLNM in the initial stages of PTC. Methods: This retrospective analysis encompassed 3,332 patients diagnosed with T1 stage PTC without evident LLNM at the time of diagnosis. These individuals underwent primary surgical intervention at West China Hospital, Sichuan University between June 2017 and February 2023. The cohort was divided into two groups: patients manifesting LLNM and those without metastasis at the time of surgery. Additionally, T1 stage PTC patients were subdivided into T1a and T1b categories. Factors influencing LLNM were scrutinized through both univariate and multivariate analyses. Results: The incidence of LLNM was observed in 6.2% of the cohort (206 out of 3,332 patients). Univariate analysis revealed significant correlations between LLNM and male gender (P<0.001), tumor localization in the upper lobe (P<0.001), maximal volume of the primary tumor (P<0.001), largest tumor diameter (P<0.001), multifocality (P<0.001), and bilaterality (P<0.001), with the exception of age (P=0.788) and duration of active surveillance (AS) (P=0.978). Multivariate logistic regression analysis identified male gender (P<0.001), upper lobe tumor location (P<0.001), maximal primary tumor volume (P<0.001), and multifocality (P<0.001) as independent predictors of LLNM. However, age categories (≤55, >55 years), maximum tumor diameter, bilaterality, and surveillance duration did not exhibit a significant impact. Comparative analyses between T1a and T1b subgroups showed congruent univariate results but revealed differences in multivariate outcomes. In the T1a subgroup, gender, tumor location, and multifocality (all P<0.05) were associated with elevated LLNM risk. Conversely, in the T1b subgroup, tumor location, dimensions, and multifocality (all P<0.05) were significant predictors of LLNM risk, whereas gender (P=0.097) exerted a marginal influence. Conclusions: The investigation highlights several key risk factors for LLNM in T1 stage PTC patients, including gender, upper lobe tumor location, larger tumor size, and multifocality. Conversely, prolonged AS and younger age did not significantly elevate LLNM risk, suggesting the viability of AS as a strategic option in selected cases.

Discovery of CBPD-268 as an Exceptionally Potent and Orally Efficacious CBP/p300 PROTAC Degrader Capable of Achieving Tumor Regression.

CBP/p300 proteins are key epigenetic regulators and promising targets for the treatment of castration-resistant prostate cancer and other types of human cancers. Herein, we report the discovery and characterization of CBPD-268 as an exceptionally potent, effective, and orally efficacious PROTAC degrader of CBP/p300 proteins. CBPD-268 induces CBP/p300 degradation in three androgen receptor-positive prostate cancer cell lines, with DC50 ≤ 0.03 nM and Dmax > 95%, leading to potent cell growth inhibition. It has an excellent oral bioavailability in mice and rats. Oral administration of CBPD-268 at 0.3-3 mg/kg resulted in profound and persistent CBP/p300 depletion in tumor tissues and achieved strong antitumor activity in the VCaP and 22Rv1 xenograft tumor models in mice, including tumor regression in the VCaP tumor model. CBPD-268 was well tolerated in mice and rats and displayed a therapeutic index of >10. Taking these results together, CBPD-268 is a highly promising CBP/p300 degrader as a potential new cancer therapy.

A prospective study comparing the gasless endoscopic thyroidectomy trans-axillary approach to conventional open thyroidectomy: health and quality of life outcomes.

BACKGROUND: The relationship between different surgical treatments and quality of life remains uncertain for differentiated thyroid carcinoma (DTC). The aim of this study is to compare the gasless endoscopic thyroidectomy trans-axillary approach (ET) and traditional open thyroidectomy (OT) through a prospective cohort study focusing on the rate of the efficacy, and quality of life (QoL). METHODS: This prospective observational longitudinal cohort study enrolled 134 female patients diagnosed with DTC from December 01/2021 to December 31/2022. Multiple scales were applicated to evaluate the differences in quality of life, effectiveness, safety, etc. between the two groups during preoperative and postoperative follow-up periods, including the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, version 3.0 (QOL-C30), Symptom Checklist (SCL-90), Scar Cosmesis Assessment and Rating (SCAR-Q), voice impairment score (VIS), swallowing impairment score (SIS), and neck impairment score (NIS). RESULTS: Among them, 68 accepted ET and 66 patients underwent OT. To enhance comparability between the two groups, the patients enrolled in this study are female. Compared with the OT group, the ET group performed significantly better postoperative physical quality of life, including sound (p = 0.036), swallowing (p < 0.001), and neck function (p = 0.010). The ET group was also associated with significantly better cosmetic satisfaction (p < 0.001), and relatively faster recovery in psychological and emotional situation. CONCLUSIONS: Gasless endoscopic thyroidectomy through an axillary approach leads to good cosmetic and psychological effects, improves postoperative QoL, and could be recommended for rapid postoperative recovery and involvement in daily and social activities.

Design, Synthesis, and Biological Evaluation of Potent and Selective PROTAC Degraders of Oncogenic KRASG12D.

KRASG12D, the most frequent KRAS oncogenic mutation, is a promising target for cancer therapy. Herein, we report the design, synthesis, and biological evaluation of a series of KRASG12D PROTACs by connecting the analogues of MRTX1133 and the VHL ligand. Structural modifications of the linker moiety and KRAS inhibitor part suggested a critical role of membrane permeability in the degradation activity of the KRASG12D PROTACs. Mechanism studies with the representative compound 8o demonstrated that the potent, rapid, and selective degradation of KRASG12D induced by 8o was via a VHL- and proteasome-dependent manner. This compound selectively and potently suppressed the growth of multiple KRASG12D mutant cancer cells, displayed favorable pharmacokinetic and pharmacodynamic properties in mice, and showed significant antitumor efficacy in the AsPC-1 xenograft mouse model. Further optimization of 8o appears to be promising for the development of a new chemotherapy for KRASG12D-driven cancers as the complementary therapeutic strategy to KRAS inhibition.

Bibliometric insights in advances of endoscopic thyroidectomy: research status, hotspots, and global trends.

Background: Endoscopic thyroidectomy (ET) has witnessed significant advancements over the last three decades. Various surgical methods and approaches have been developed that minimize trauma, enhance aesthetics, and reduce psychological stress caused by scars. Papillary thyroid carcinoma is the main reason for thyroidectomy and ET represents an innovative technique for treating thyroid cancer. In this study, nearly three decades of scientific articles were analyzed and summarized to gain a better understanding by using bibliometric method. Methods: A total of 486 publications between 1996 and 2023 were retrieved from the Web of Science database through systematic searches. The objective of this study involved characterizing general information and investigating developmental trends and research frontiers. CiteSpace was employed to evaluate and visualize the results. Results: The query resulted 486 publications with a total citation frequency of 10,202. The top five countries in terms of the number of published articles were China, South Korea, the USA, Italy, and Japan. The top five countries in terms of literature centrality were Scotland, Israel, Brazil, the USA, and France. There were eight institutions with more than ten publications. The top ten institutions had a centrality score of 0.02 or above, indicating intensive research in this area and substantial collaboration among institutions. The most cited authors primarily originated from South Korea. Journals such as Surgical Endoscopy and Other Interventional Techniques, Surgical Laparoscopy Endoscopy & Percutaneous Techniques, Head and Neck Journal for the Sciences and Specialties of the Head and Neck, and Thyroid exerted considerable influence in this field. Keyword analysis results revealed that research predominantly focused on thyroid cancer and surgical approaches. Conclusions: This bibliometric study provides a comprehensive analysis of global productivity, collaboration, and research focus in the field of ET. The findings of this study serve as valuable guidance for future research in ET.

Beyond the Square knot: A validation study for a novel knot-tying method named "inverse 9".

Purpose: We compared the "inverse 9" laparoscopic suturing and knot-tying (LSKT) method to the traditional LSKT method in a validation study to demonstrate the "inverse 9" method's superiority and effectiveness in laparoscopy. Methods: On the basis of their experience in laparoscopic surgery, 78 trainees were divided into two groups, with 52 inexperienced trainees in group A and 26 experienced trainees in group B. In group A, 52 trainees were randomly allocated to either group A1 ("inverse 9" LSKT training) or group A2 (traditional LSKT training). In group B, experienced trainees were randomly assigned to receive "inverse 9" LSKT training (group B1) or continuing training in the traditional LSKT method (group B2). All trainees received the same instruction and assessment and were asked to provide a subjective assessment of the two training methods at the end of the training. Results: The trainees in groups A1, A2, and B had similar average ages and were mostly male. After training, all showed preliminary mastery of LSKT (P < 0.05). The trainees in groups A1 and B1 achieved learning proficiency in the fifth assessment, while those in group A2 achieved it in the sixth assessment. The trainees in groups A1 and B1 showed lower difficulty in achieving mastery and lower operation fatigue scores (P < 0.05), and 61.50 % of the trainees in group B preferred the "inverse 9" method in subjective evaluation. Conclusion: As a novel LSKT technique, "inverse 9" offers a multitude of benefits. In addition to ensuring a simpler operation and effectively reducing the knot-tying time, it also involves a shorter learning curve than traditional LSKT methods. As such, it can be easily mastered and widely adopted as a standard LSKT technique.

Discovery of ARD-1676 as a Highly Potent and Orally Efficacious AR PROTAC Degrader with a Broad Activity against AR Mutants for the Treatment of AR + Human Prostate Cancer.

We report herein the discovery and extensive characterization of ARD-1676, a highly potent and orally efficacious PROTAC degrader of the androgen receptor (AR). ARD-1676 was designed using a new class of AR ligands and a novel cereblon ligand. It has DC50 values of 0.1 and 1.1 nM in AR+ VCaP and LNCaP cell lines, respectively, and IC50 values of 11.5 and 2.8 nM in VCaP and LNCaP cell lines, respectively. ARD-1676 effectively induces degradation of a broad panel of clinically relevant AR mutants. ARD-1676 has an oral bioavailability of 67, 44, 31, and 99% in mice, rats, dogs, and monkeys, respectively. Oral administration of ARD-1676 effectively reduces the level of AR protein in the VCaP tumor tissue in mice and inhibits tumor growth in the VCaP mouse xenograft tumor model without any sign of toxicity. ARD-1676 is a highly promising development candidate for the treatment of AR+ human prostate cancer.

Preoperative preparation for Graves' disease.

Thyroidectomy is always regarded as the crucial treatment for Graves' disease, especially in cases of poor efficacy or excessive side effects of antithyroid- drugs and 131I radioiodine therapy. To decrease the incidence of hemorrhage, thyroid storms and other severe complications during the perioperative period, surgeons explore different therapies to prepare for thyroidectomy. We performed a review of preoperative preparation with a focus on the Graves' disease population. Most of the previous schemes are effective, which contributes to the smooth operation of patients, but there is no unified standard for preoperative preparation. This review aims to summarize the preoperative preparation of Graves' disease and the latest developments. Prospective studies with longer follow up-up periods are required to select appropriate preoperative regimens based on personal thyroid statements and to identify target populations of benefit.

Sensitivities evaluation of five radiopharmaceuticals in four common medullary thyroid carcinoma metastatic sites on PET/CT: a network meta-analysis and systematic review.

OBJECTIVES: Detecting medullary thyroid carcinoma (MTC) metastatic lesions accurately is still a challenge for clinicians. PET/computed tomography (PET/CT) seems to be the most effective method in recent years. However, the sensitivity of each radiopharmaceutical varies greatly in different metastatic sites. We aim to investigate and compare five novel and common PET or PET/CT radiopharmaceutical sensitivities at the four most frequent metastatic sites by network meta-analysis. METHODS: We searched for studies evaluating PET/CT radiopharmaceutical sensitivities at different metastatic sites in PubMed, Web of Science, Embase, and Cochrane Library. The risk bias was analyzed, and publication bias was accessed by funnel plot asymmetry tests. We performed both global inconsistency and local inconsistency tests by evaluating the agreement between direct and indirect comparisons. Then, we made pairwise meta-analyses and network meta-analyses for each metastatic site. Finally, we performed the surface under the cumulative ranking curves (SUCRA) and calculated the SUCRA values to rank the probability of each radiopharmaceutical being the most sensitive method. RESULTS: In our results, 243 patients from 9 clinical studies which accessed sensitivities of different radiopharmaceuticals in MTC metastatic sites were included. For lymph nodes and liver, TF2/ 68 Ga-SSM288 showed the highest SUCRA values (0.974 in lymph nodes, 0.979 in liver). The SUCRA values for 18 F-DOPA and 68 Ga-SSA for bone metastatic lesions were nearly identical (0.301 and 0.319, respectively) and were higher than the other three radiopharmaceuticals. For lung lesions, 11 C-methionine had the highest SUCRA value (0.412). CONCLUSION: TF2/ 68 Ga-SSM288 had the best sensitivity in lymph nodes and liver lesions. 11 C-methionine was most sensitive in lung lesions. While 18 F-DOPA and 68 Ga-SSA had familiar sensitivities to be the best two radiopharmaceuticals.

Discovery of ERD-3111 as a Potent and Orally Efficacious Estrogen Receptor PROTAC Degrader with Strong Antitumor Activity.

Estrogen receptor α (ERα) is a prime target for the treatment of ER-positive (ER+) breast cancer. Despite the development of several effective therapies targeting ERα signaling, clinical resistance remains a major challenge. In this study, we report the discovery of a new class of potent and orally bioavailable ERα degraders using the PROTAC technology, with ERD-3111 being the most promising compound. ERD-3111 exhibits potent in vitro degradation activity against ERα and demonstrates high oral bioavailability in mice, rats, and dogs. Oral administration of ERD-3111 effectively reduces the levels of wild-type and mutated ERα proteins in tumor tissues. ERD-3111 achieves tumor regression or complete tumor growth inhibition in the parental MCF-7 xenograft model with wild-type ER and two clinically relevant ESR1 mutated models in mice. ERD-3111 is a promising ERα degrader for further extensive evaluations for the treatment of ER+ breast cancer.

Endoscopic Gasless Trans-Axillary Parathyroidectomy for Patients with Primary Hyperparathyroidism: An Observational Retrospective Study.

Objective: The objective of this study is to evaluate the efficacy and safety of the gasless trans-axillary parathyroidectomy approach for the treatment of primary hyperparathyroidism in our medical center. Methods: A retrospective analysis was conducted on patients with single parathyroid adenoma who underwent parathyroidectomy using the gasless trans-axillary approach. Results: Between June 2020 and June 2022, 41 patients (37 women and 4 men) with primary hyperparathyroidism underwent endoscopic parathyroidectomy utilizing the gasless trans-axillary approach. Postoperative levels of parathyroid hormone and calcium showed a significant decline following the procedure. No permanent damage to the recurrent laryngeal nerve was observed. The mean adenoma size was 19.2 mm, with a volume of 2.66 mL. Successful identification and resolution of hyperparathyroidism were achieved for all patients. Conclusions: Endoscopic gasless trans-axillary parathyroidectomy is a safe and viable option for patients with primary hyperparathyroidism who wish to avoid cervical scarring. The surgical outcomes were favorable, and no major complications were encountered.

Discovery of ARD-2051 as a Potent and Orally Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of Androgen Receptor for the Treatment of Advanced Prostate Cancer.

We report the discovery of ARD-2051 as a potent and orally efficacious androgen receptor (AR) proteolysis-targeting chimera degrader. ARD-2051 achieves DC50 values of 0.6 nM and Dmax >90% in inducing AR protein degradation in both the LNCaP and VCaP prostate cancer cell lines, potently and effectively suppresses AR-regulated genes, and inhibits cancer cell growth. ARD-2051 achieves a good oral bioavailability and pharmacokinetic profile in mouse, rat, and dog. A single oral dose of ARD-2051 strongly reduces AR protein and suppresses AR-regulated gene expression in the VCaP xenograft tumor tissue in mice. Oral administration of ARD-2051 effectively inhibits VCaP tumor growth and causes no signs of toxicity in mice. ARD-2051 is a promising AR degrader for advanced preclinical development for the treatment of AR+ human cancers.

Stimuli-activatable PROTACs for precise protein degradation and cancer therapy.

The proteolysis targeting chimeras (PROTACs) approach has attracted extensive attention in the past decade, which represents an emerging therapeutic modality with the potential to tackle disease-causing proteins that are historically challengeable for conventional small molecular inhibitors. PROTAC harnesses the endogenic E3 ubiquitin ligase to degrade protein of interest (POI) via ubiquitin-proteasome system in a cycle-catalytic manner. The event-driven pharmacology of PROTAC is poised to pursue those targets that are conventionally undruggable, which enormously extends the space of drug development. Furthermore, PROTAC has the potential to address drug resistance of small molecular inhibitors by degrading the whole POI. Nevertheless, PROTACs display high-efficiency and always-on properties to degrade POI, they may cause severe side effects due to an "on-target but off-tissue" protein degradation profile at the undesirable tissues and cells. Given that, the stimuli-activatable PROTAC prodrugs have been recently exploited to confine precise protein degradation of the favorable targets, which may conquer the adverse effects of PROTAC due to uncontrollable protein degradation. Herein, we summarized the cutting-edge advances of the stimuli-activatable PROTAC prodrugs. We also overviewed the progress of PROTAC prodrug-based nanomedicine to improve PROTAC delivery to the tumors and precise POI degradation in the targeted cells.

Discovery of a Potent, Cooperative, and Selective SOS1 PROTAC ZZ151 with In Vivo Antitumor Efficacy in KRAS-Mutant Cancers.

The linker moiety of a proteolysis-targeting chimera (PROTAC) molecule plays a critical role in modulating the degradation activity, target selectivity, and physico-chemical properties. However, the basics and underlying mechanisms of chemical modifications of the linker structure causing dramatic changes in the PROTAC degradation activity warrant further investigation. Herein, we report the design and characterization of a highly potent and selective SOS1 PROTAC ZZ151. After systematically modifying the linker length and composition, we observed that subtle modification of just one atom of the linker moiety of ZZ151 resulted in remarkable changes in the formation of the ternary complex and thus dramatically affected the degradation activities. ZZ151 quickly, specifically, and effectively induced SOS1 degradation; displayed potent antiproliferation activities against a broad panel of KRAS mutant-driven cancer cells; and showed superior anticancer activities in the KRASG12D- and G12V-mutant xenografts in mice. ZZ151 is a promising lead for developing new chemotherapies targeting KRAS mutants.