Chemical Space of FLT3 Inhibitors as Potential Anti-AML Drugs

Abstract

Although some of those compounds expressed potent bioactivities and have reached the advanced clinical trials for the treatment of leukemia, there are still several problems need to be faced before they enter the market eventually, especially the drug resistance issue. The improvement of therapeutic potency for FLT3 inhibitors might depend on the useful combination therapy and further refinement of the intrinsic properties of FLT3 inhibitors.

Discovery of 5-trifluoromethyl-2-aminopyrimidine derivatives as potent dual inhibitors of FLT3 and CHK1

“…9–11 Subsequently, a large number of FLT3 inhibitors (FLT3i) have been exploited for the treatment of AML, in response to the high correlation between FLT3 and AML. 12 The first-generation FLT3i were multitarget and nonselective inhibitors, including midostaurin, 9 which possibly caused off-target side effects. The second-generation FLT3i had better specificity and less toxicity, such as gilteritinib 13 and quizartinib 14 (Fig.…”

“…6-Bromo-1-(cyclopropylsulfonyl)-1,2,3,4-tetrahydroquinoline (11) Yellowish oil; yield: 44%; 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.49 (d, J = 8.5 Hz, Ar-H, 1H), 7.39 (d, J = 2.5 Hz, Ar-H, 1H), 7.32 (dd, J = 8.5, 2.0 Hz, Ar-H, 1H), 3.70-3.68 (m, CH 2 , 2H), 2.83 (t, J = 7.0 Hz, CH 2 , 2H), 2.77-2.72 (m, CH, 1H), 1.98-1.93 (m, CH 2 , 2H), 0.97-0.92 (m, CH 2 × 2, 4H); LC-MS (ESI †): m/z calcd. for C 12 H 14 BrNO 2 S: 314.99 [M + H] + ; found: 317.13, 319.13.6-Bromo-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline(12) White solid; yield: 51%; 1 H NMR (500 MHz, DMSO-d 6 ) δ 7. 1H), 5H), 7.38 (dd, J = 9.0, 2.5 Hz, 1H), 1H), (m, CH 2 , 2H), 2.44-2.39 (m, CH 2 , 2H), 1.60-1.51 (m, CH 2 , 2H); LC-MS (ESI): m/z calcd.…”

<p>PRKD2 Promotes Progression and Chemoresistance of AML via Regulating Notch1 Pathway</p>

“…It has been reported that AML is the most common cause of leukemia-related mortality in adult patients with a 5-year overall survival (OS) around 40% 3. Despite the use of new target drugs such as FLT3 inhibitors and IDH1/2 inhibitors in the clinic, the mainstay of treatment approach is chemotherapy and several chemotherapeutic drugs including anthracycline are predominantly used 4–6. Although great prognostic improvement of AML has been made during the past few decades, 60–80% of patients who have initially achieved complete remission finally relapse while parts of them eventually die of this disease due to chemoresistance 7.…”