Uncompetitive nanomolar dimeric indenoindole inhibitors of the human breast cancer resistance pump ABCG2

Article abstract of DOI:10.1016/j.ejmech.2020.113017

Multidrug resistance membrane pumps reduce the efficacy of chemotherapies by exporting a wide panel of structurally-divergent drugs. Here, to take advantage of the polyspecificity of the human Breast Cancer Resistance Protein (BCRP/ABCG2) and the dimeric nature of this pump, new dimeric indenoindole-based inhibitors from the monomeric α,β-unsaturated ketone 4b and phenolic derivative 5a were designed. A library of 18 homo/hetero-dimers was synthesised. Homo-dimerization shifted the inhibition efficacy from sub-micromolar to nanomolar range, correlated with the presence of 5a, linked by a 2–6 methylene-long linker. Non-toxic, the best dimers displayed a therapeutic ratio as high as 70,000. It has been found that the high potency of the best compound 7b that displays a K_I of 17 nM is due to an uncompetitive behavior toward mitoxantrone efflux and specific for that drug, compared to Hoechst 33342 efflux. Such property may be useful to target such anticancer drug efflux mediated by ABCG2. Finally, at a molecular level, an uncompetitive mechanism by which substrate promotes inhibitor binding implies that at least 2 ligands should bind simultaneously to the drug-binding pocket of ABCG2.

Full text of DOI:10.1016/j.ejmech.2020.113017

J O U R N A L O F T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y , V O L . 6 7 , N O . 1 6 , S U P P L S , 2 0 1 6
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Case Summary. This case represents the possibility that hinge motion
could make coronary artery dissection at the edge of stent. We found the
dissection thirty minutes later despite IVUS couldn’t show any injury in the
first PCI. It may be a risk factor to place stent edge in tortuous vessels with
hinge motion. Additionally, a biolimus-eluting stent (NOBORI, TERUMO)
has thicker strut (125
mm) than other second-generation drug-eluting
stents, which may be also the risk of the phenomenon.
TCTAP C-112
A Complex Calcified Lesion: A Lesson Learnt Twice!
Aaron Wong1
1National Heart Centre Singapore, Singapore
[CLINICAL INFORMATION]
Patient initials or identifier number. DDC
Relevant clinical history and physical exam. 83 year-old man with car-
diovascular risk factors of DM, HTN and HLP. He had past history IHD
with previous PCI done in 2000. He presented 3 years ago with recent
onset of chest tightness on exertion and coronary angiography
showed triple vessel disease. LAD and RCA were both stented with
DES. LCX was calcified and diffusely disease and was left for medical
treatment. 8 months later he presented with exertional angina and he
was admitted for coronary angiography.

J O U R N A L O F T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y , V O L . 6 7 , N O . 1 6 , S U P P L S , 2 0 1 6
S226
Relevant catheterization findings. Coronary angiography showed both
LAD and RCA stents were patent. The LCX was diffusely disease with
significant lesions from proximal to distal.
The decision was for PCI to LCX.
[INTERVENTIONAL MANAGEMENT]
Procedural step. Right radial approach with used with 6 French XB 3
guiding catheter. LCX was wired but the balloon was difficult to pass
to the distal lesion despite using buddy wire technique. 1.0 mm
balloon also failed to cross. Wire was exchanged for Rotalink wire and
1.25 mm burr was used. However, the rotablator burr was stucked in
the mid LCX at first pass. Attempted to pullback was unsuccessful but
the bur was able to push forward. A few runs were made to the distal
LCX. With a bit of force the burr was removed from the vessel.
Although 2.0 mm balloon was able to dilate the proximal and mid LCX,
there was another tight spot in distal LCX. Same burr was used to for the
distal LCX. The burr was again stuck in the distal LCX after the first pass.
However this time, it was not possible to remove even with brute force.
The distal LCX flow was compromised and patient was having chest pain.
A 7 French XB3 catheter was introduced through right femoral approach
and LCX was wired. The intent was to wire the LCX passing the stuck burr
and put a balloon down to dilate the lesion and release the burr. However
the wire was unable to go distal LCX but a side branch near the stuck burr.
Balloon was delivered and dilated within the LCX near the burr. After the
dilatation, with some force, the rotablator burr was successfully removed
from the LCX.
The lesion was rewired and with high pressure NC balloon, the
lesion was successful dilated and stented with 2 DES.
Case Summary. Severely calcified lesion is challenging and procedure
may be prolonged or even failed. In our case, the lesion was severely
calcified and rotablation was mandatory to achieve an optimal
outcome. Even with the smallest burr, it was stuck, not once but
twice, in the LCX.
There are many methods to remove stuck burr. If a wire and balloon
can pass the stuck burr, dilatation at the site will release the burr.
However, the lesions are usually too tight for anything to cross.
Balloon dilatation adjacent to the stuck burr may also break the cal-
cium at the plaque and release the burr. In our case, there was a side
branch near the burr which we could use to dilate and release the burr.
TCTAP C-113
A Lesson to Learn from an Octogenarian with STEMI
Yuet-Wong Cheng1
1Queen Elizabeth Hospital, Hong Kong, China
[CLINICAL INFORMATION]
Patient initials or identifier number. WSK
Relevant clinical history and physical exam. Ms. W was 85 years old with
past medical history of diabetes mellitis, hypertension and dementia.