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.

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.

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.

Design, synthesis and structure-activity relationship studies of pyrido[2,3-d]pyrimidin-7-ones as potent Janus Kinase 3 (JAK3) covalent inhibitors.

Aberrantly activated Janus kinase 3 (JAK3) has been constantly detected in various immune disorders and hematopoietic cancers, suggesting its potential of being an attractive therapeutic target for these indications. Clinical benefits of drugs selectively targeting JAK3 versus pan-JAK inhibitors remain unclear. In this study, we report the design and synthesis of a new series of JAK3 covalent inhibitors with a pyrido[2,3-d]pyrimidin-7-one scaffold. After the extensive SAR study, compound 10f emerged to be the most potent JAK3 inhibitor with an IC50 value of 2.0 nM. It showed excellent selectively proliferation inhibitory activity against U937 cells harboring JAK3 M511I mutation, while remained weakly active to the other tested cancer cells. Compound 10f also dose-dependently inhibited the phosphorylation of JAK3 and its downstream signal STAT5 in U937 cells. Taken together, 10f may serve as a promising tool molecule for treating cancers with aberrantly activated JAK3.

Design of the First-in-Class, Highly Potent Irreversible Inhibitor Targeting the Menin-MLL Protein-Protein Interaction.

The structure-based design of M-525 as the first-in-class, highly potent, irreversible small-molecule inhibitor of the menin-MLL interaction is presented. M-525 targets cellular menin protein at sub-nanomolar concentrations and achieves low nanomolar potencies in cell growth inhibition and in the suppression of MLL-regulated gene expression in MLL leukemia cells. M-525 demonstrates high cellular specificity over non-MLL leukemia cells and is more than 30 times more potent than its corresponding reversible inhibitors. Mass spectrometric analysis and co-crystal structure of M-525 in complex with menin firmly establish its mode of action. A single administration of M-525 effectively suppresses MLL-regulated gene expression in tumor tissue. An efficient procedure was developed to synthesize M-525. This study demonstrates that irreversible inhibition of menin may be a promising therapeutic strategy for MLL leukemia.

[Detection of Chlorpyrifos on Spinach Based on Surface Enhanced Raman Spectroscopy with Silver Colloids].

In this research, the surface enhanced Raman spectroscopy (SERS) technique is used to develop a nondestructive and fast detecting method for the detection of residual chlorpyrifos on spinach. Silver colloids used for SERS spectroscopy is prepared by the reduction of silver nitrate with hydroxylamine hydrochloride at alkaline pH. The prepared silver colloids are dropped onto spinach samples, then the SERS spectra are collected non-destructively with a self-developed Raman system. This method can be made without physical contact to samples, and rapidly completed without time-consuming sample pre-treatments, and suited to the development of real-time on-line detection methods for trace pesticide residues. SERS signals are collected from 20 points on each spinach sample with 450 mW laser power and 2.5 s exposure time. Chlorpyrifos concentrations in 24 samples are determined with gas chromatography after SERS spectra taken. Savitzky-Golay (SG) smoothing filter and effective peak linear fitting method are used to remove the random noise and the fluorescence background for improving the accuracy of SERS results. The SERS signals are collected from different parts of 50 spinach samples with the same concentration of chlorpyrifos but at different fresh degrees. The relative standard deviation (RSD) of chlorpyrifos' characteristic peak intensities is 13.4%. Although the differences of samples lead to differences in the curves of Raman spectrum, they have little influence on the characteristic peak intensities, which indicates the stability of the proposed detecting method. After the fluorescent background removed, the 20 curves of each sample are averaged. Correlation analysis is done between chlorpyrifos concentration and signal intensity at every Raman shift. Results show that correlation coefficients are higher than 0.85 in the range of 615.5~626.4 cm-1. Signals in this range are used to establish multiple linear regression (MLR) model for the prediction of residual chlorpyrifos. MLR model was developed for chlorpyrifos concentration versus Raman signal intensity at 615.5~626.4 cm-1 for predicting residual chlorpyrifos content in samples, the correlation coefficients of calibration (RC) and validation (RP) are 0.961 and 0.954, which indicate a good linear relationships between them. The minimum detectable threshold for this method is 0.05 mg·kg-1 which is close to the value limited by the national standard of China (0.1 mg·kg-1 for chlorpyrifos in spinach). The proposed practical method is sample, fast, without sample preparation, thus it shows great potential in safety detection of fruits and vegetables.

[Simultaneous Detection of Multiple Quality Parameters of Pork Based on Fused Dual Band Spectral].

For dual band visible/near infrared spectroscopy system (350~1 100 and 1 000~2 500 nm), there exsits a band overlap and for the same sample the reflectivity data were unlike due to the performance difference between instruments. A band connection and data fusion method was proposed in this paper to make better use of the dual-band data. A dual-band visible/near-infrared spectroscopy system was built in the study to collect 60 pork samples' reflectance spectra. The reflectance spectra of samples were performed with pretreatment methods of Savitzky-Golay (S-G) and standard normal variable transform to eliminate the spectral noise. Then partial least squares regression (PLSR) prediction models of pork quality attributes (color, pH and cooking loss) based on single-band spectrum and dual-band spectrum were established, respectively. For the cross of two band overlap, the data were connected and integrated using the method put forward in this paper and then PLSR models were established based on the integrated data. The PLSR model yielded prediction result with correlation coefficient of validation (R(p)) of 0.948 8, 0.920 0, 0.950 5, 0.930 1 and 0.903 5 for L(*), a(*), b(*), pH value and cooking loss, respectively. To simplify the model, uninformative variables elimination (UVE) was employed to select characteristic variables. The experimental results show that the proposed method was able to achieve a better fusion of the two band spectral data, and it was good for the establishment of a more simplified and better prediction model.

[A Point Raman Scanning Method for Rapidly Detection of Spinach Quality and Safety Parameters].

According to actual market demand for nondestructive detection of vegetables quality and safety, combined with the heterogeneity of quality and safety parameters such as pesticide residues on leaf vegetables surface and to realize the automatic point scanning for the whole leaf vegetables samples, a suction device based on laboratory (self-designed) Raman spectroscopy hardware and a GUI application software based on the LabVIEW development platform were developed. This system can test the Raman spectroscopy of the whole spinach including the automatic collection, display and storage of the Raman signal of all the scanned points by set up different scan step. A new method to remove the Raman spectrum background was proposed based on data replacement with linear equation at the range of threshold spectrum on both sides of the effective peaks according to the characteristics of spinach original spectra. Its principle is to determine the starting position of linear fitting by judging whether there is trough on both sides of the crest, and then to generate and replace the original spectra data in peak position through the linear fitting equation. Spinach samples were used for the experiment showed that the chlorophyll content and distribution of chlorpyrifos pesticide residue on each scanning point can be obtained after scanning. Therefore, the point scanning Raman system could improve detection accuracy of the quality and safety parameters for the non-uniform samples effectively.

[Research on Identification and Determination of Pesticides in Apples Using Raman Spectroscopy].

Raman spectroscopy combined with chemometric methods has been thought to an efficient method for identification and determination of pesticide residues in fruits and vegetables. In the present research, a rapid and nondestructive method was proposed and testified based on self-developed Raman system for the identification and determination of deltamethrin and acetamiprid remaining in apple. The peaks of Raman spectra at 574 and 843 cm(-1) can be used to identify deltamethrin and acetamiprid, respectively, the characteristic peaks of deltamethrin and acetamiprid were still visible when the concentrations of the two pesticides were 0.78 and 0.15 mg · kg(-1) in apples samples, respectively. Calibration models of pesticide content were developed by partial least square (PLS) algorithm with different spectra pretreatment methods (Savitzky-Golay smoothing, first derivative transformation, second derivative transformation, baseline calibration, standard normal variable transformation). The baseline calibration methods by 8th order polynomial fitting gave the best results. For deltamethrin, the obtained prediction coefficient (Rp) value from PLS model for the results of prediction and gas chromatography measurement was 0.94; and the root mean square error of prediction (RMSEP) was 0.55 mg · kg(-1). The values of Rp and RMSEP were respective 0.85 and 0.12 mg · kg(-1) for acetamiprid. According to the detect performance, applying Raman technology in the nondestructive determination of pesticide residuals in apples is feasible. In consideration of that it needs no pretreatment before spectra collection and causes no damage to sample, this technology can be used in detection department, fruit and vegetable processing enterprises, supermarket, and vegetable market. The result of this research is promising for development of industrially feasible technology for rapid, nondestructive and real time detection of different types of pesticide with its concentration in apples. This supplies a rapid nondestructive and environmentally friendly way for the determination of fruit and vegetable quality and safety.

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.

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.

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.

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.

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.

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.

Design, Synthesis, and Bioevaluation of Pyrido[2,3-d]pyrimidin-7-ones as Potent SOS1 Inhibitors.

The use of small molecular modulators to target the guanine nucleotide exchange factor SOS1 has been demonstrated to be a promising strategy for the treatment of various KRAS-driven cancers. In the present study, we designed and synthesized a series of new SOS1 inhibitors with the pyrido[2,3-d]pyrimidin-7-one scaffold. One representative compound 8u showed comparable activities to the reported SOS1 inhibitor BI-3406 in both the biochemical assay and the 3-D cell growth inhibition assay. Compound 8u obtained good cellular activities against a panel of KRAS G12-mutated cancer cell lines and inhibited downstream ERK and AKT activation in MIA PaCa-2 and AsPC-1 cells. In addition, it displayed synergistic antiproliferative effects when used in combination with KRAS G12C or G12D inhibitors. Further modifications of the new compounds may give us a promising SOS1 inhibitor with favorable druglike properties for use in the treatment of KRAS-mutated patients.

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.

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.