Discovery of a Diaminopyrimidine FLT3 Inhibitor Active against Acute Myeloid Leukemia

Profiling of the kinase-binding capabilities of an aminopyrimidine analogue detected in a cellular screen of the St. Jude small-molecule collection led to the identification of a novel series of FMS-like tyrosine kinase 3 (FLT3) inhibitors. Structure–activity relationship studies led to the development of compounds exhibiting good potency against MV4-11 and MOLM13 acute myelogenous leukemia cells driven by FLT3, regardless of their FLT3 mutation status. In vitro pharmacological profiling demonstrated that compound <b>5e</b> shows characteristics suitable for further preclinical development

Discovery of a Diaminopyrimidine FLT3 Inhibitor Active against Acute Myeloid Leukemia

Profiling of the kinase-binding capabilities of an aminopyrimidine analogue detected in a cellular screen of the St. Jude small-molecule collection led to the identification of a novel series of FMS-like tyrosine kinase 3 (FLT3) inhibitors. Structure–activity relationship studies led to the development of compounds exhibiting good potency against MV4-11 and MOLM13 acute myelogenous leukemia cells driven by FLT3, regardless of their FLT3 mutation status. In vitro pharmacological profiling demonstrated that compound <b>5e</b> shows characteristics suitable for further preclinical development

Synthetic pathways to analogs 44–55.

<p>Reagents and conditions: (a) MeOH, SOCl₂ (b) LDA. MeI, THF, −78°C (c) KOH, EtOH/H₂O (d) HATU, DIEA, MeCN.</p

Discovery of a Diaminopyrimidine FLT3 Inhibitor Active against Acute Myeloid Leukemia

Profiling of the kinase-binding capabilities of an aminopyrimidine analogue detected in a cellular screen of the St. Jude small-molecule collection led to the identification of a novel series of FMS-like tyrosine kinase 3 (FLT3) inhibitors. Structure–activity relationship studies led to the development of compounds exhibiting good potency against MV4-11 and MOLM13 acute myelogenous leukemia cells driven by FLT3, regardless of their FLT3 mutation status. In vitro pharmacological profiling demonstrated that compound <b>5e</b> shows characteristics suitable for further preclinical development

Synthesis and Evaluation of Sulfonylnitrophenylthiazoles (SNPTs) as Thyroid Hormone Receptor–Coactivator Interaction Inhibitors

We previously identified a series of methylsulfonylnitrobenzoates (MSNBs) that block the interaction of the thyroid hormone receptor with its coactivators. MSNBs inhibit coactivator binding through irreversible modification of cysteine 298 of the thyroid hormone receptor (TR). Although MSNBs have better pharmacological features than our first generation inhibitors (β-aminoketones), they contain a potentially unstable ester linkage. Here we report the bioisosteric replacement of the ester linkage with a thiazole moiety, yielding sulfonylnitrophenylthiazoles (SNPTs). An array of SNPTs representing optimal side chains from the MSNB series was constructed using parallel chemistry and evaluated to test their antagonism of the TR-coactivator interaction. Selected active compounds were evaluated in secondary confirmatory assays including regulation of thyroid response element driven transcription in reporter constructs and native genes. In addition the selected SNPTs were shown to be selective for TR relative to other nuclear hormone receptors (NRs)

Structures of a diverse set of compounds selected for screening.

<p>Structures of a diverse set of compounds selected for screening.</p

FtsZ interdomain cleft site region residues implicated in inhibitor binding.

<p>FtsZ interdomain cleft site region residues implicated in inhibitor binding.</p

<i>Mtb</i> H₃₇Rv and BJ cell data of Sulindac sulfide amide derivatives 18–37.

<p><i>Mtb</i> H₃₇Rv and BJ cell data of Sulindac sulfide amide derivatives 18–37.</p

Screening and Development of New Inhibitors of FtsZ from <i>M</i>. <i>Tuberculosis</i> - Fig 14

<p><b>Docked poses of (A) 24 (carbon atoms colored cyan) and (B) Colchicine (carbons colored orange).</b> All other atoms are colored by atom type (C green, O red, N blue, S yellow). H-bonds are indicated with dashed lines. (C) Docked poses of <b>24</b> and Colchicine displayed simultaneously show overlap of similar pharmacophoric features.</p

<i>Mtb</i> H₃₇Rv and BJ cell data of extended Sulindac sulfide amide derivatives 56–57.

<p><i>Mtb</i> H₃₇Rv and BJ cell data of extended Sulindac sulfide amide derivatives 56–57.</p