Browsing by Author "Abdel-Aziz, Amal Kamal"

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Insights into the design of inhibitors of the EGFR family with anticancer activity overcoming resistance: a case of optimizing thieno[2,3-d]pyrimidine-based EGFR inhibitors
(Elsevier, 02/03/2022) Milik, Sandra N; Abdel-Aziz, Amal Kamal; El-Hendawy, Morad M; El-Gogary, Riham I; Saadeldin, Mona Kamal; Minucci, Saverio; Klein, Christian D; Abouzid, Khaled A.M
EGFR inhibitors have been in clinical use for the treatment of non-small cell lung cancer and breast cancer for years. However, generation after generation of the developed EGFR inhibitors have been met by clinical resistance. In an attempt to develop the next generation of EGFR inhibitors, compound (2) was selected as a lead for optimization. (2) was identified during a previous study for the development of thieno[2,3-d]pyrimidine-based dual EGFR/HER2 inhibitors where it demonstrated good dual EGFR/HER2 inhibition and selective anti-proliferative activity against the lapatinib-sensitive cancer cell lines. Additionally, it showed modest activity against the T790M/L858R EGFR mutant. Twelve derivatives based on (2) were designed with the aim of optimizing the enzymatic and cellular activity of (2). Those twelve derivatives were prepared and tested for their inhibitory activities against EGFR, HER2 and T790M/L858R, and for their anti-proliferative activity against the cancer cell lines A431 and MDA-MB-468, and the NCI-60 panel of human cancer cell lines. The results provide an insight into the structural features required for EGFR/HER2 inhibition, and the conclusions drawn from this study could help direct future development of EGFR inhibitors that can overcome the current resistance mechanisms.
nsights into the design of inhibitors of the EGFR family with anticancer activity overcoming resistance: A case of optimizing thieno[2,3-d]pyrimidine-based EGFR inhibitors
(Elsevier, 02/03/2022) Milik, Sandra N; Abdel-Aziz, Amal Kamal; El-Hendawy, Morad M; El-Gogary, Riham I; Saadeldin, Mona Kamal; Minucci, Saverio; Klein, Christian D; Abouzid, Khaled A.M
EGFR inhibitors have been in clinical use for the treatment of non-small cell lung cancer and breast cancer for years. However, generation after generation of the developed EGFR inhibitors have been met by clinical resistance. In an attempt to develop the next generation of EGFR inhibitors, compound (2) was selected as a lead for optimization. (2) was identified during a previous study for the development of thieno[2,3-d]pyrimidine-based dual EGFR/HER2 inhibitors where it demonstrated good dual EGFR/HER2 inhibition and selective anti-proliferative activity against the lapatinib-sensitive cancer cell lines. Additionally, it showed modest activity against the T790M/L858R EGFR mutant. Twelve derivatives based on (2) were designed with the aim of optimizing the enzymatic and cellular activity of (2). Those twelve derivatives were prepared and tested for their inhibitory activities against EGFR, HER2 and T790M/L858R, and for their anti-proliferative activity against the cancer cell lines A431 and MDA-MB-468, and the NCI-60 panel of human cancer cell lines. The results provide an insight into the structural features required for EGFR/HER2 inhibition, and the conclusions drawn from this study could help direct future development of EGFR inhibitors that can overcome the current resistance mechanisms. © 2022
Tuning mTORC1 activity dictates the response of acute myeloid leukemia to LSD1 inhibition
(NLM (Medline), 08/01/2020) Abdel-Aziz, Amal Kamal; Pallavicini, Isabella; Ceccacci, Elena; Meroni, Giuseppe; Saadeldin, Mona Kamal; Varas, Mario; Minucci, Saverio
Lysine specific demethylase-1 (LSD1) has been shown to be critical in acute myeloid leukemia (AML) pathogenesis and this has led to the development of LSD1 inhibitors (LSD1i) which are currently tested in clinical trials. Nonetheless, preclinical studies reported that AML cells frequently exhibit intrinsic resistance to LSD1 inhibition, and the molecular basis for this phenomenon is largely unknown. We explored the potential involvement of mammalian target of rapamycin (mTOR) in mediating the resistance of leukemic cells to LSD1i. Strikingly, unlike sensitive leukemias, mTOR complex 1 (mTORC1) signaling was robustly triggered in resistant leukemias following LSD1 inhibition. Transcriptomic, chromatin immunoprecipitation and functional studies revealed that insulin receptor substrate 1(IRS1)/extracellular-signal regulated kinases (ERK1/2) signaling critically controls LSD1i induced mTORC1 activation. Notably, inhibiting mTOR unlocked the resistance of AML cell lines and primary patient-derived blasts to LSD1i both in vitro and in vivo In conclusion, mTOR activation might act as a novel pro-survival mechanism of intrinsic as well as acquired resistance to LSD1i, and combination regimens co-targeting LSD1/mTOR could represent a rational approach in AML therapy. Copyright© 2020 Ferrata Storti Foundation