Breast cancer (BC) is currently the most devastating condition in women globally. The American Cancer Society anticipated that 13 % (about 1 in 8) of U.S. women are going to develop invasive BC in the course of their life with approximately 287,850 new cases that are expected to be diagnosed annually, then 3 % (1 in 39) of that cases will die from the disease in their lifetime [1]. An appraised 30 % of BC cases are attributed to modifiable risk factors that should be avertible such as physical inactivity, excess body weight, and rising alcohol intake [2]. Also, it is believed that most of the BC cases exhibit an inimitable pattern of receptor overexpression and most of these cases are frequently linked with a dysregulation in hormonal receptors such as estrogen and progesterone receptors beside the membrane tyrosine kinase pertaining to EGFR [3]. The EGFR or HER family that was customarily reported to be overexpressed in BC, is composed of 4 tyrosine kinase receptors, that are known as EGFR/ErbB1/HER1, ErbB2/HER2, ErbB3/HER3 and ErbB4/HER4 [4]. The EGFR and/or HER2 are usually expressed at low levels in normal cells, so their overexpression is a distinctive attribute of BC existence [5]. Upregulation or mutation of EGFR is found in 15–30 % of BCs and linked to large tumors, whereas HER2 overexpression caused by HER2 gene amplification, reported in 20–30 % of BC cases, thus they are protruded in recent years as critical and validated targets for BC therapies [6]. EGFR and HER2 catalyze phosphorylation reactions in signaling cascades that affect every aspect of cell growth, differentiation and transduction [7]. They govern the extracellular ligand domain, hydrophobic transmembrane domain and intracellular tyrosine kinase domain where an adenosine triphosphate (ATP) binding site is extant [8]. Together EGFR and HER-2 heterodimerize to preserve better binding enhancement of the epidermal growth factor (EGF) ligand or other related ligands causing transfer of terminal phosphate group from ATP to a specific protein substrate, they are called tyrosine kinase receptors due to the tyrosine amino acid that phosphorylates [9]. Therefore, dual inhibition of both EGFR and HER-2 is an attractive trajectory as potential BC therapy [10].

Tyrosine kinase inhibitors are generally divided into 2 classes; antibodies that perform indirect inhibitory effect by hindering the EGF ligands binding to the extracellular domain of the EGFR such as cetuximab and panitumumab, and small molecules inhibitors that act directly through binding to the ATP binding site of the intracellular tyrosine kinase domain [11]. Accordingly, the 4-anilinoquinazoline scaffolds are the most commonly used candidates as EGFR/HER-2 dual inhibitors. In contrast, lapatinib member was the 1st clinically approved drug by FDA in 2007 for treatment of BC through targeting the ATP binding pocket of the kinase domain [12]. The ATP binding pocket of the kinase domain accommodates 2 different conformations, namely the active and the inactive conformations, wherever the high selectivity is accomplished through targeting the inactive conformation binding domain [13]. Regard to that, lapatinib has been designated to target the inactive conformation through prominent hydrophobic contact of its 3-flurobenzyloxy group to the closer gatekeeper residues. Inappropriately, it was revealed that gatekeeper acquires certain mutations such as EGFRT790M/HER-2T7981(M) through replacing the smaller Thr798 residue with the bulkier Ile798 or Met798 residues, which cause uncomplimentary steric clashes with the 3-flurobenzyloxy group, and that confer the most common clinical resistance against lapatinib [14,15], beside the serious drawbacks that have been triggered by lapatinib such as gastrointestinal inconvenience and skin toxicity [16]. Consequently, designing novel compounds by replacing the quinazoline core of lapatinib with an appropriate isostere, in addition to swapping of 3-flurobenzyloxy group by another pharmacophore, may diminish the steric clashes within the gatekeeper of the inactive conformation and afford better treatment outcomes with reduced side effects.

Lately, pyrazolo[3,4-d]pyrimidine scaffold was reported to overcome the acquired drug resistance in EGFR tyrosine kinase domain from the fact that, pyrazolo[3,4-d]pyrimidine is considered an adenine bioisostere and can imitate critical ATP interaction with the kinase domain such as compounds Ia-c, II and III, illustrated in (Fig. 1) [17,18].

From another perspective, the increment of thiazole nucleus to quinazoline scaffold was reported to exhibit considerable anticancer potential through the intensification of the dual inhibition activity of EGFR/HER-2 tyrosine kinases as present in compounds IV and V (Fig. 2) [19].

Motivated by the aforementioned facts, we intended to assess the anticancer potential of lapatinib based compounds through the isosteric replacement of quinazoline moiety with pyrazolo[3,4-d]pyrimidine nucleus, beside the replacement of 3-flurobenzyloxy group of lapatinib by different previously reported pharmacophores that protrude protein kinase inhibition activities, such as hydrazones [20], thiazoles [19,21], 1,3,4-thiadiazoles and 1,2,4-triazoles [22]; compounds 8a-g, 10a-h, 11a,b and 12a,b respectively, with the retention of 4-anilino group (Fig. 3).

In sum, our approach is focused on creating a range of lapatinib-based compounds with some structural flexibility. This flexibility may reduce the steric clashes within the gatekeeper mutant amino acids, which would improve treatment options for resistant BC cell lines and reduce the likelihood of side effects that need more attention in the future.