Rac and Cdc42, are homologous GTPases that regulate cell migration, invasion, and cell-cycle progression; thus, representing key targets for metastasis therapy. We previously reported on the efficacy of MBQ-167, which blocks both Rac1 and Cdc42 in breast cancer cells and mouse models of metastasis. To identify compounds with increased activity, a panel of MBQ-167 derivatives was synthesized, maintaining its 9-ethyl-3-(1H-1,2,3-triazol-1-yl)-9H-carbazole core. Similar to MBQ-167, MBQ-168 and EHop-097 inhibit activation of Rac and Rac1B splice variant and breast cancer cell viability, and induce apoptosis. MBQ-167 and MBQ-168 inhibit Rac and Cdc42 by interfering with guanine nucleotide binding, and MBQ-168 is a more effective inhibitor of P21-activated kinase (1–3) activation. EHop-097 acts via a different mechanism by inhibiting the interaction of the guanine nucleotide exchange factor Vav with Rac. MBQ-168 and EHop-097 inhibit metastatic breast cancer cell migration, and MBQ-168 promotes loss of cancer cell polarity to result in disorganization of the actin cytoskeleton and detachment from the substratum. In lung cancer cells, MBQ-168 is more effective than MBQ-167 or EHop-097 at reducing ruffle formation in response to EGF. Comparable with MBQ-167, MBQ-168 significantly inhibits HER2-positive tumor growth and metastasis to lung, liver, and spleen. Both MBQ-167 and MBQ-168 inhibit the cytochrome P450 (CYP) enzymes 3A4, 2C9, and 2C19. However, MBQ-168 is approximately 10× less potent than MBQ-167 at inhibiting CYP3A4, thus demonstrating its utility in relevant combination therapies. In conclusion, the MBQ-167 derivatives MBQ-168 and EHop-097 are additional promising antimetastatic cancer compounds with similar and distinct mechanisms.Significance: Targeting the related GTPases Rac and Cdc42 that regulate cancer metastasis is a viable strategy to impede metastasis of solid cancers. Herein, we describe new Rac and Cdc42 inhibitors with unique mechanisms and varying potency in different cancer cell lines. The MBQ-167 derivatives MBQ-168 and EHop-097 show promise as potential antimetastatic cancer agents.

Background: Although the overall colorectal cancer (CRC) incidence has been steadily declining in the United States, a dramatic increase in the number of CRC cases among individuals younger than 50 years of age (early‐onset CRC) has been observed. CRC is the second and first leading cause of cancer death in the United States and among Hispanic men and women living in Puerto Rico (PRH), respectively. We report CRC incidence rates from 2000 to 2021 among PRH and compare them to data in the Surveillance, Epidemiology, and End Results Program (SEER).Methods: Data on colorectal adenocarcinomas diagnosed between January 1, 2000, and December 31, 2021, were obtained from the Puerto Rico Central Cancer Registry and SEER17, including race and ethnicity. Age‐standardized incidence rates were calculated using the direct method. The Joinpoint Regression Program calculated temporal trends on CRC incidence rates based on age‐adjusted Average Annual Percent Change (AAPC) estimates.Results: A total of 729,479 incident cases of CRC were analyzed. US Hispanics had the highest percentage of early‐onset CRC (EOCRC) cases (17.0%) among the racial and ethnic groups studied. PRH had the highest age‐standardized EOCRC incidence rate (12.18 per 100,000 persons) and the highest increase in EOCRC incidence temporal trends (AAPC = 2.68; 95% CI: 1.83 to 3.51).Conclusions: A significantly higher increase in EOCRC incidence was observed among Hispanic populations. Future studies should disaggregate Hispanic subpopulations by considering the country of ancestral origin, which will help identify specific risk factors and exposures and aid in developing tailored prevention and risk stratification strategies to reduce EOCRC incidence.

Colorectal cancer (CRC) is the leading cause of cancer-related death in Puerto Rico, a U.S. territory with noted disparities in CRC incidence, particularly among those with early-onset disease (EOCRC). Although EOCRC incidence has been consistently increasing in the U.S. mainland, and a disparate burden has been reported among Hispanics, EOCRC mortality and survival are yet to be assessed among Hispanics living in Puerto Rico (PRH). In this study, we analyzed EOCRC mortality and survival trends in PRH and compared these to those of other U.S. populations. Mortality data were obtained from the Puerto Rico Central Cancer Registry and the Surveillance, Epidemiology, and End Results (SEER) program. Descriptive characteristics and temporal trends were derived via SEER*Stat software (version 9.0.42) and Joinpoint regression models, respectively. Relative survival was estimated using the Actuarial method and the Ederer II approach. Overall, CRC mortality trends showed a decline, but an increase in EOCRC mortality among Hispanics. PRH exhibited the lowest 5-year survival in regional cancers (54.10%), with NHB having the lowest survival among younger individuals. This study highlights significant disparities in EOCRC mortality trends and underscores an urgent need for targeted public health strategies and research efforts to address the disproportionate burden of EOCRC among PRH.

Rac and Cdc42, are homologous GTPases that regulate cell migration, invasion, and cell-cycle progression; thus, representing key targets for metastasis therapy. We previously reported on the efficacy of MBQ-167, which blocks both Rac1 and Cdc42 in breast cancer cells and mouse models of metastasis. To identify compounds with increased activity, a panel of MBQ-167 derivatives was synthesized, maintaining its 9-ethyl-3-(1H-1,2,3-triazol-1-yl)-9H-carbazole core. Similar to MBQ-167, MBQ-168 and EHop-097 inhibit activation of Rac and Rac1B splice variant and breast cancer cell viability, and induce apoptosis. MBQ-167 and MBQ-168 inhibit Rac and Cdc42 by interfering with guanine nucleotide binding, and MBQ-168 is a more effective inhibitor of P21-activated kinase (1–3) activation. EHop-097 acts via a different mechanism by inhibiting the interaction of the guanine nucleotide exchange factor Vav with Rac. MBQ-168 and EHop-097 inhibit metastatic breast cancer cell migration, and MBQ-168 promotes loss of cancer cell polarity to result in disorganization of the actin cytoskeleton and detachment from the substratum. In lung cancer cells, MBQ-168 is more effective than MBQ-167 or EHop-097 at reducing ruffle formation in response to EGF. Comparable with MBQ-167, MBQ-168 significantly inhibits HER2-positive tumor growth and metastasis to lung, liver, and spleen. Both MBQ-167 and MBQ-168 inhibit the cytochrome P450 (CYP) enzymes 3A4, 2C9, and 2C19. However, MBQ-168 is approximately 10× less potent than MBQ-167 at inhibiting CYP3A4, thus demonstrating its utility in relevant combination therapies. In conclusion, the MBQ-167 derivatives MBQ-168 and EHop-097 are additional promising antimetastatic cancer compounds with similar and distinct mechanisms.Significance:Targeting the related GTPases Rac and Cdc42 that regulate cancer metastasis is a viable strategy to impede metastasis of solid cancers. Herein, we describe new Rac and Cdc42 inhibitors with unique mechanisms and varying potency in different cancer cell lines. The MBQ-167 derivatives MBQ-168 and EHop-097 show promise as potential antimetastatic cancer agents.

Supplemental Table 1: Effect of MBQ-167 on Rho GTPase activity (Active Rho GTPase/Total Rho GTPase) following 24 h in MDA-MB-231 cells, relative to vehicle (=1); Supplemental Table 2: Effect of MBQ-167 on Rac activity (Active Rac/Total Rac) following 24 h in MCF-7 cells; Supplemental Table 3: Optimal %Treated (T)/Control (C) for mammary fat pad tumor growth for EHop-167 treated nude mice; Supplemental Table 4: Tumor growth delay for EHop-167-treated mice